Uterine first pass effect in postmenopausal women.

BACKGROUND: Vaginally administered drugs distribute preferentially to the uterus; counter-current transfer from the vaginal veins to the uterine artery probably plays a pivotal role. In each side, the ovarian and uterine arteries form arterial anastomoses and controversy exists regarding the origin of the arterial supply to the Fallopian tube and tubal part of the uterus, and consequently whether these tissues can be reached through vaginal administration. METHODS: A thermocatheter with four measurement points, each separated by 5 mm, was inserted under endoscopic control into the tubal corner of uterus in 10 conscious, menopausal women and the temperatures registered every 2 s. The vagina was then flushed for 15 min with 1.5 l of saline at room temperature, after which the probe position was re-assessed by the endoscope. RESULTS: The lowest measurement point (15 mm from the tip) cooled significantly more than the other points (P < 0.0001). At 15 min, mean temperature reduction at point 4 was significantly greater than at all other measurement points (P < 0.05) due to local transfer of cold from vaginal vein blood to the uterine arterial blood (but not the ovarian artery). CONCLUSIONS: The results support the theory that, at least in postmenopausal women, the uterine artery supplies most of the uterus while the corneal part of cavity (up to 5-10 mm from the ostium) receives the blood supply from the ovarian artery. This finding represents a rationale for vaginal administration of drugs when a local effect on the uterus (e.g. progestational or relaxation) in postmenopausal women is requested.

Model of counter-current transfer from vagina to urethra in postmenopausal women.

BACKGROUND: Low-dose vaginal oestrogens are effective in treating post-menopausal urogenital atrophy without inducing endometrial proliferation. We aimed to assess whether this dichotomic effect could be the result of a preferential vagina-to-urethra transfer via a counter-current transfer of oestrogens from vagina to the arterial blood supplying the urethra. Due to the impossibility of obtaining blood samples from urethral arteries, and since the nature of counter-current exchange of substances is similar to the transfer of heat, we investigated cold transfer throughout the anterior vaginal wall to the vesical trigone and urethra. METHODS: Plastic tubes filled with cold saline were inserted into the vagina of 30 menopausal women. Temperatures were recorded at the vesical trigone and at three different urethral sites. Comparisons were performed 2 and 4.5 min after starting of cooling, and 4.5 min after removal of tubes. RESULTS: The urethra cooled significantly more than the bladder. Urethral cooling was not homogeneous; distal sites of the urethra cooled significantly more than proximal site and bladder despite a larger distance to the vaginal cooling device. CONCLUSIONS: Distribution of cold from the vagina to the urethra is not the result of simple diffusion and mechanisms of preferential distribution may exist from the vagina to the middle and low part of the urethra.

Tolerability of the mini-pan-endoscopic approach (transvaginal hydrolaparoscopy and minihysteroscopy) versus hysterosalpingography in an outpatient infertility investigation.

OBJECTIVE: To compare the acceptance and tolerability of the mini-pan-endoscopic approach (transvaginal hydrolaparoscopy [THL] combined with minihysteroscopy) versus hysterosalpingography (HSG) for evaluating tubal patency and the uterine cavity in an outpatient infertility investigation. DESIGN: Randomized controlled study. SETTING: University hospital. PATIENT(S): Twenty-three infertile patients without obvious pelvic pathology. INTERVENTION(S): Women were randomly divided into two groups. One group underwent minihysteroscopy and THL with tube chromoperturbation as first investigation and HSG within the following 7 days, while in the other group the investigation sequence was inverted. Women reported pain experienced before and at the end of procedures. MAIN OUTCOME MEASURE(S): Mean duration of procedures, level of pain experienced, diagnostic agreement about tubal patency and uterine cavity normality. RESULT(S): THL and minihysteroscopy took significantly more time but was significantly less painful than HSG. Regarding tubal patency, in 95.5% of cases THL agreed with HSG. In one case, HSG diagnosed a bilateral obstruction of tubes, whereas at THL a bilateral spreading of methylene blue was seen. Agreement on intrauterine pathologies between minihysteroscopy and HSG was poor (43%); the number of intrauterine abnormalities found at hysteroscopy was significantly greater than at HSG. CONCLUSION(S): THL in association with minihysteroscopy provided more information and was better tolerated than HSG in an outpatient infertility investigation.

Preferential vascular-based transfer from vagina to the corpus but not to the tubal part of the uterus in postmenopausal women.

BACKGROUND: Vaginal administration of progesterone during infertility treatment has therapeutic advantages over oral administration. However, the reasons for this are poorly defined. To demonstrate a preferential vagina-to-uterus distribution of substances, we investigated cold distribution from vagina to the uterus and rectum. METHOD: In 10 postmenopausal women, thermoprobes were inserted into the uterine cavity and in the rectum at <9 cm or at >9 cm from the anus; temperatures were subsequently measured during 10 min flushing of vagina with cold saline. RESULTS: After 10 min, temperature decreased as follows: uterus, tubal angle: -0.22 +/- 0.07 degrees C, 10 (mean +/- SEM, n); uterus, middle cavity: -1.26 +/- 0.34 degrees C, 9; rectum, <9 cm insertion: -3.69 +/- 0.68 degrees C, 3; rectum, >9 cm insertion: -0.51 +/- 0.19 degrees C, 6. CONCLUSIONS: Despite obviously different distances to the vagina of the uterine and the low rectal probes (<9 cm) the temperature decrease occurred at the same time. Cold transfer from vagina to the uterus and rectum is probably not the result of simple diffusion but of a vascular counter-current transfer. Differential cooling of corpus and tubal angles suggests a different arterial supply; while uterine corpus is supplied from the uterine artery, the tubal angles seem to be mainly supplied from the ovarian artery via the tubal arcade.

Effects of estrogen therapy on arterial resistance and pulsatility in postmenopausal women.

The hypothesis of this study was that changes in arterial determinants of afterload due to static muscular contraction can be modified, in postmenopausal women, by estrogen replacement therapy. Two groups of 14 postmenopausal and 15 premenopausal women were enrolled. Hemodynamic changes induced by right handgrip were recorded between days 7 and 10 of the menstrual cycle in premenopausal women. The same recordings were performed in postmenopausal women, before and after receiving transdermal estrogen replacement therapy for 8 days. Handgrip was performed at 50% of maximal voluntary contraction and maintained until exhaustion. Arterial pressure and blood velocity were recorded in the resting hand with photoplethysmographic and Doppler techniques. Indices of arterial elasticity and resistance were calculated. In postmenopausal women, these indices increased during effort only slightly less after therapy than before, if the mean values and statistical significance were considered, but the most evident effect of therapy was a decrease in interindividual differences in the effort induced changes. This means that, after therapy, increases in arterial resistance and elasticity indices were appreciably prevented mainly in those postmenopausal women who, before therapy, showed the greatest increases. Differences due to therapy were negligible in postmenopausal women in whom, before estrogen replacement, increases in elasticity and resistance indices during effort were similar to those obtained in premenopausal women. After therapy, no differences were found in resting conditions in any of the investigated cardiovascular parameters. Estrogen replacement did not appreciably affect changes in some arterial afterload-related indexes during handgrip, if the average values were considered in a group of postmenopausal women, but uneven and unpredictable peaks in individual responses were cut off, with a better predictability of the responses to sustained muscular contractions, as well as of the related risk factors.

Mechanisms of uterine specificity of vaginal progesterone.

Endometrial transformations achieved by vaginal progesterone exceed those normally expected from the circulating concentrations obtained, this suggests some degree of direct vagina to uterus transport. We speculate on the different mechanisms involved in uterine specificity of vaginal progesterone and report data of a preliminary randomized study comparing progesterone concentrations in serum and endometrial tissue obtained from hysterectomy specimens after vaginal or i.m. administration. Eight post-menopausal women undergoing transabdominal hysterectomy were randomized to receive either vaginal progesterone gel, 90 mg, or i.m. progesterone formulation, 50 mg, at 08.00 and 20.00 on the day before surgery and at 06.00 on the day of surgery. Venous blood samples for progesterone measurement were drawn at 08.00 on the day before surgery and during the surgery. Endometrial progesterone concentrations were markedly higher in women who received vaginal progesterone (1.38+/-0.66 and 0.38+/-0.19 ng/mg protein, for vaginal and i.m. groups respectively) (P < 0.02) despite lower serum concentrations (4.17 < 0.56 and 32.32+/-11.06 ng/ml, for vaginal and i.m. groups respectively) (P < 0.001). The vaginal route induces endometrial progesterone concentrations that far exceed those expected from the serum progesterone concentrations achieved.

Beneficial effects of postmenopausal hormone replacement therapy with transdermal estradiol on sensitivity to activated protein C.

Many hemostatic and fibrinolytic parameters have been evaluated following hormone replacement therapy (HRT) but little is known about its influence on the anticoagulant response to activated protein C (APC-sensitivity). For this purpose, we studied the effect of transdermal 17-beta-estradiol (50 microg/24 h) by a continuous regimen on the APC-sensitivity, in 28 postmenopausal hysterectomized women (mean age, 47 years; range, 44-65 years). We also measured the plasma proteins directly involved in the protein C anticoagulant pathway, such as activities of factor VIII (VIII:C), factor V and free protein S. Von Willebrand factor (vWF) antigen, the carrier protein of factor VIII, was also determined. Blood sampling was done at baseline and after 16-week therapy. A significant increase in the normalized APC-sensitivity ratio (n-APC-SR) values (mean +/- SD: pre-trial, 0.88 +/- 0.14; post-trial, 1.01 +/- 0.12; P < 0.001) and a significant decrease of factor VIII:C plasma levels (pre-trial, 1.13 +/- 0.29 IU/ml; post-trial, 0.98 +/- 0.20 IU/ ml; P = 0.001) were found. No difference was observed in factor V, protein S and vWF plasma levels. Correlation studies demonstrated only a significant negative correlation between the percent change in n-APC-SR and the percent change in factor VIII:C (r = -0.574; P = 0.001). Our findings clearly show that HRT with transdermal estradiol improves the anticoagulant response to APC, probably as a result of a decreased factor VIII:C. We also suggest that a similar but opposite mechanism may occur for perorally administered estrogens used in the HRT. These results may have some clinical implications about the reported increase of the risk for venous thromboembolism following HRT.

Direct transport of progesterone from vagina to uterus.

OBJECTIVE: To compare progesterone concentrations in serum and endometrial tissue from hysterectomy specimens after vaginal or intramuscular (IM) administration of progesterone gel. METHODS: This was a randomized open study of 14 post-menopausal women undergoing transabdominal hysterectomies. Participants received either vaginal progesterone gel, 90 mg, or IM progesterone, 50 mg, at 8:00 AM and 8:00 PM on the day before surgery and at 6:00 AM on the day of surgery. Venous blood samples for progesterone measurement were collected at 8:00 AM on the day before surgery (baseline) and during surgery. After removal of the uterus, the endometrium was sampled from the anterior and posterior walls. Results were expressed as ratios of endometrial to serum progesterone concentrations x 100. RESULTS: Ratios of endometrial to serum progesterone concentrations were markedly higher in women who received vaginal progesterone (14.1 median, 8.5-59.4 range; 95% confidence interval [CI] 9.89, 38.79) compared with IM injections (1.2 median, 0.5-13.1 range; 95% CI -0.48, 7.39) (P < .005). CONCLUSION: Ratios of endometrial to serum progesterone concentrations were higher after vaginal administration of progesterone than after IM injections. Our findings in endometrial tissue specimens from hysterectomies excluded the possibility of contamination by progesterone that remained in the vagina.

Different plasma levels of nitric oxide in arterial and venous blood.

Experimental investigations suggest that a basal release of nitric oxide (NO) occurs in arterial but not in venous endothelium. We therefore decided to compare plasma levels of NO in the arterial and venous circulation. Parallel blood samples were drawn from the radial artery and brachial vein in 15 healthy drug-free women. Nitric oxide levels were assessed by measuring plasma levels of nitrite and nitrate, the two stable oxidation products of NO metabolism. Plasma levels of NO metabolites in arterial blood were significantly higher than in the paired venous blood samples (45.1 +/- 17.7 versus 22.5 +/- 8.5 mumol l-1, respectively, mean +/- SD). The results of this preliminary study strongly suggest that the endothelial release of NO is probably different in arteries and veins in vivo; this is also consistent with previous literature indicating that basal release of NO occurs mainly from the endothelium of arteries but not from that of veins.

Resectoscopic treatment of uterus didelphys with unilateral imperforate vagina complicated by hematocolpos and hematometra: case report.

OBJECTIVE: To describe a technique for treating hematocolpos and hematometra in patients with uterus didelphys and unilateral imperforate vagina involving the use of resectoscopy under ultrasonographic control. DESIGN: Case report. SETTING: University hospital. PATIENT(S): A 13-year-old girl with uterus didelphys with unilateral hematometra, hematocolpos, and ipsilateral renal agenesis. The girl complained of severe abdominal pain, which appeared with each of her menses. INTERVENTION(S): The intervention was performed by a vaginoscopic approach to preserve the integrity of the hymen. The first incision on the vaginal wall was performed in correspondence with the hematocolpos under continuous ultrasonographic guidance with the use of a straight resectoscopic loop. Resection of the vaginal septum was continued with the use of an angled resectoscopic loop until almost complete excision of the septum was achieved. MAIN OUTCOME MEASURE(S): Clinical, echographic, and vaginoscopic findings before the operation and 2 and 6 months after the operation. RESULT(S): The surgical procedure was easy to perform. Almost complete excision of the septum was achieved with just a few passages of the resectoscope. Complete drainage of both the hematocolpos and the hematometra was confirmed by ultrasonography. The postoperative period was completely uneventful. Clinical and vaginoscopic evaluations 6 months after the operation confirmed the integrity of the hymen, the complete resolution of clinical symptoms, and the persistence of a large communication between the two vaginas. CONCLUSION(S): Resectoscopic excision under ultrasonographic guidance of the vaginal septum in a girl with uterus didelphys with unilateral hematometra and hematocolpos was effective and easy to perform, and it fully respected the integrity of the reproductive system.

Effects of estrogen replacement therapy on plasma levels of nitric oxide in postmenopausal women.

OBJECTIVE: Our purpose was to assess the effects of estrogen replacement therapy on plasma levels of nitric oxide in postmenopausal women. STUDY DESIGN: The study, designed as a randomized, double-blind placebo-controlled crossover trial, involved 28 healthy postmenopausal women who had previously undergone hysterectomy. Women received either transdermal estradiol (50 g/day) (estradiol group) or placebo (placebo group) for 6 months continuously. At the end of month 6 the treatment allocations were opened, and then the treatments were exchanged for 1 month. The serum concentration of estradiol was measured at baseline before treatment and at the end of months 6 and 7. The plasma concentration of the stable oxidation products of nitric oxide was assessed before treatment and monthly until month 7. RESULTS: The mean baseline concentrations of nitric oxide metabolites in the estradiol and placebo groups were similar (mean and SD: 19+/-4.3 vs 21+/-5.6 micromol/L, respectively). At subsequent measurements from months 1 to 6, the mean concentration of nitric oxide metabolites increased significantly in the estradiol group alone, in which the concentration ranged between 33 6.4 and 36 8.5 micromol/L. At the end of month 7 the mean level of nitric oxide metabolites in women previously treated with estradiol fell to baseline value (19 2.6 micromol/L), whereas in the placebo group the level increased significantly (34 4.4 micromol/L). CONCLUSION: Estrogen replacement therapy induces a sustained increase in plasma levels of nitric oxide in postmenopausal women; the suspension of estrogen replacement therapy is followed by a significant reduction in nitric oxide levels. The results of this study suggest that a nitric oxide-related mechanism may help to explain the cardioprotective effect of estrogen replacement therapy in the postmenopausal period.

Effects of short-term transdermal estradiol administration on plasma levels of nitric oxide in postmenopausal women.

OBJECTIVE: To assess the effects of short-term transdermal E2 administration on nitric oxide (NO) plasma levels in postmenopausal women. DESIGN: Randomized, placebo-controlled trial. SETTING: Healthy volunteers in an academic research environment. PATIENT(S): Twenty-eight healthy postmenopausal women. INTERVENTION(S): Transdermal administration of E2 (100 microg/d) or placebo on days 1 and 4 of a 1-week treatment regimen. MAIN OUTCOME MEASURE(S): Serum concentrations of E2 and plasma concentrations of NO stable oxidation products were assessed on day 1, before placement of the patch, and subsequently on days 2, 3, and 6. RESULT(S): The mean concentration of NO metabolites on days 2, 3, and 6 was significantly greater in the E2 group (40.08+/-15.42 micromol/L, 38.05+/-18.82 micromol/L, and 42.03+/-16.81 micromol/L on days 2, 3, and 6, respectively) compared with both baseline levels (23.07+/-5.79 micromol/L) and the placebo group (23.51+/-4.06 micromol/L, 21.64+/-4.72 micromol/L, and 21.81+/-4.46 micromol/L on days 2, 3, and 6, respectively). CONCLUSION(S): During a 1-week treatment regimen with transdermal E2, plasma levels of NO in postmenopausal women were significantly higher than baseline levels on days 2, 3, and 6. This suggests that the effect of estrogens on NO synthesis is rapid and that it is maintained with repeated administration.

Circulating levels of nitric oxide in fertile women in relation to the menstrual cycle.

OBJECTIVE: To investigate nitric oxide (NO) production in the two phases of normal menstrual cycle. DESIGN: Prospective clinical study. SETTING: Normal human volunteers in an academic research environment. PATIENT(S): Fifteen normally cycling women. INTERVENTION(S): Follicle growth monitoring by ultrasound, serum, and plasma sampling in the midfollicular phase, at ovulation, and in the midsecretory phase. MAIN OUTCOME MEASURE(S): Plasma concentration of NO stable oxidation products and serum concentrations of E2 and P. RESULT(S): Plasma concentration of NO metabolites resulted higher in the follicular phase with respect to the secretory phase and peaked at midcycle. CONCLUSION(S): The results strongly support the existence of an E2 control of NO production and release. The significant reduction in NO metabolites observed in the secretory phase suggests a possible opposing action of P on either NO production or release.

Effects of continuous percutaneous estradiol administration on skeletal turnover in postmenopausal women: a 1-year prospective controlled study.

The aim of this study was to investigate the short and long term effects of continuous percutaneous administration of estradiol (E2) cream on skeletal turnover in women in surgical postmenopause. Forty women were randomly divided into two groups, one treated with a single daily application of 3 mg/day E2 cream continuously for 12 months, the other receiving placebo cream. Forearm densitometry was performed before and at the end of treatment. Serum E2, osteocalcin (BGP), alkaline posphatase (AP) and urinary N-telopeptide of type I collagen (NTX) were also measured at baseline, month 4 and 12 of the protocol. At month 4, bone turnover was also assessed by evaluating 99mtechnetium-methylene diphosphonate (99mTc-MDP) skeletal uptake. Changes in E2, BGP, AP and NTX as well as 99mTc-MDP skeletal uptake in hormone group vs. placebo were significant after 4 months of treatment. At month 12, proximal site densitometry showed no variation in either group whereas the percentage of variation in distal site measurements resulted significantly different with an increase in the hormone group and a reduction in the placebo group. In conclusion continuous percutaneous administration of E2 cream was effective in rapidly reducing bone turnover in postmenopausal women and in counteracting the accelerated postmenopausal bone loss.

Transabdominal sonohysterography, transvaginal sonography, and hysteroscopy in the evaluation of submucous myomas.

OBJECTIVE: To assess the usefulness of transabdominal sonohysterography in the diagnosis and evaluation of submucous myomas. METHODS: Fifty-two premenopausal women hospitalized for hysterectomy for benign gynecologic indications underwent preoperative conventional transvaginal sonography, transabdominal sonohysterography, and hysteroscopy. The results of the three techniques in terms of diagnosis, size, intracavitary growth, and location of the submucous myomas were compared with those revealed by direct inspection of the surgical specimens. RESULTS: Conventional transvaginal sonography for the diagnosis of submucous myomas had a sensitivity of 90% and a specificity of 98%; the predictive values of abnormal and normal scans were 90 and 98%, respectively. Transabdominal sonohysterography had sensitivity, specificity, and predictive values of 100%, as did hysteroscopy. In all cases, the sonographic techniques measured tumor size more accurately than did hysteroscopy. The transabdominal sonohysterography measurements differed from direct evaluation by no more than 2 mm, and the hysteroscopic measurements were significantly different from those of the surgical specimens. The sonohysterographic evaluation of intrauterine growth was significantly more precise than that of the other techniques, differing from direct measurements by no more than 5-10%. Conventional transvaginal sonography failed to localize three of 11 myomas; hysteroscopy and transabdominal sonohysterography provided the exact location in all cases. CONCLUSION: Transabdominal sonohysterography is the most accurate technique for detecting submucous myomas and evaluating their size, intracavitary growth, and location.

Bone metabolism changes after transdermal estradiol dose reduction during estrogen replacement therapy: a 1-year prospective study.

Twenty-four surgically menopausal women were randomly allocated to one of two transdermally-administered estrogen replacement therapies (ERT): Group A was administered Estradiol (E2) TTS 0.05 mg/day for 6 months and 0.025 mg/day for the following six months and group B, E2 TTS 0.10 mg/day for the first 6 months and 0.05 mg/day for the following 6 months. For both groups, the treatment regimen was based upon the twice-weekly application of transdermal patches to the lower abdomen for three weeks a month. Serum E2, alkaline phosphatase (AP), osteocalcin (BGP) and urinary hydroxyproline (OHP) excretion levels were measured before the operation, at the beginning of ERT and after 6 and 12 months of treatment. Bone mineral density (BMD) in the distal regions of the forearms was measured by single photon absorptiometry at the start of the study and after 6 and 12 months. In Group A, both mean cortical and trabecular BMD had increased by, respectively, 1.53% and 2.17% after 6 months of therapy; after the second 6 months a significant decrease was observed in both parameters (2.40% and 3.62%, respectively). In Group B, mean cortical and trabecular BMD increased by 1.50% and 2.10%, respectively (significant increase in trabecular bone) after the first 6 months of treatment; after the following 6 months, these values persisted (+0.15 and -0.03%, respectively). Mean AP, OHP and BGP serum levels rose after the operation. In Group A, AP and OHP showed a significant decrease after the first 6 months (-34.90% and -30.90%), followed by an increase at the last evaluation of 22.50% and 35.50%, that reached statistical significance only for OHP.(ABSTRACT TRUNCATED AT 250 WORDS)

Sonohysterography versus hysteroscopy for diagnosing endouterine abnormalities in fertile women.

OBJECTIVES: To evaluate the usefulness of abdominal and vaginal sonohysterography (SHG) (considered both singly and in combination) for the diagnosis of intrauterine abnormalities. METHODS: At the Department of Obstetrics and Gynecology, University of Bari, Italy, the results of the abdominal and vaginal SHG were retrospectively compared with those of conventional transvaginal sonography and hysteroscopy in 35 fertile women in whom a hysteroscopy was indicated. The sensitivity and specificity for the diagnosis of intrauterine abnormalities of both kinds of SHG (considered both singly and in combination), transvaginal sonography and hysteroscopy were compared; the predictive values of abnormal and normal SHG were determined by a 2 x 2 table relating the test results to the patients' abnormalities shown at hysteroscopy. RESULTS: The combination of both abdominal and vaginal SHG had a sensitivity of 95% and a specificity of 100%; the predictive value of an abnormal test was 100% and that of a normal test 94%. CONCLUSIONS: SHG provides a reliable diagnosis of intrauterine abnormalities. However, hysteroscopy and guided biopsies remain the decisive diagnostic test for investigating intrauterine abnormalities.

Nasal spray administration of unmodified progesterone: evaluation of progesterone serum levels with three different radioimmunoassay techniques.

A 11.20 mg dose of progesterone was administered by nasal spray (NS) to six healthy postmenopausal women. Serial blood samples were collected and plasma progesterone was assayed by radioimmunoassay (RIA) according to three different procedures. In the first, RIA was carried out directly on plasma aliquot (Method A), in the second after diethyl ether extraction (Method B) and the third, after diethyl ether extraction and Celite column chromatography (Method C). The mean serum peak level (CMax) calculated with Method A (2.87 +/- 1.14 ng/ml) was higher than that obtained with both Method B (2.24 +/- 0.76 ng/ml) and C (1.58 +/- 0.76 ng/ml; P < 0.05); similarly the area under the curve (AUC) measured with Method A (695.79 +/- 348.24 ng h/ml) was higher than that obtained with both Method B (390.12 +/- 95.16 ng h/ml) and C (243.71 +/- 82.97 ng h/ml; P < 0.02). On the other hand, progesterone serum levels measured with Method C peaked earlier than those observed with Methods B and A (21.67 +/- 19.40, 25.83 +/- 18.55 and 35 +/- 20.70 min, respectively). These data are consistent with the high specificity of Method C for progesterone whereas the other methods could overestimate the progesterone serum levels probably measuring also progesterone metabolites particularly 5 alpha- and 5 beta-dihydroprogesterone. This study confirmed the rapid absorption of progesterone across the nasal mucosa avoiding the first-pass liver metabolism; however, a 'first-pass effect' of the nasal mucosa should be taken into consideration when progesterone is delivered by the nasal route because probably a significant portion of progestational effects are due to its active metabolites.