The objective was to verify the hypothesis of a 'first uterine pass effect' or direct preferential vagina-to-uterus transport, suggested by the evidence of higher than expected uterine tissue concentrations after vaginal administration of progesterone; we used a human ex-vivo uterine perfusion model. A mixture of tritiated (3H) and unlabelled progesterone was applied to the cuff of vaginal tissue remaining attached to the cervix after hysterectomy. At the end of the perfusion period (up to 12 h), 3H and 14C radioactivity was measured in samples of uterine tissue. Tritiated water and [14C]dextran were tested to determine the extent of non-specific vagina-to-uterus transport (leaks). Finally, sections of uterine tissue exposed only to [3H]progesterone were prepared for autoradiography. By 4-5 h after application progesterone had diffused to the entire uterus and had reached a steady state; 4 h after application, progesterone concentrations reached 185 +/- 155 and 254 +/- 305 ng/100 mg of endometrial and myometrial tissue respectively. Endometrial extraction of progesterone was higher when the experiment was performed on uteri obtained during the luteal phase (280 +/- 156 ng/100 mg of endometrial tissue) than those removed during the proliferative phase of the menstrual cycle (74 +/- 28 ng/100 mg of endometrial tissue). These data demonstrate that a 'first uterine pass effect' occurs when drugs are delivered vaginally, thereby providing an explanation for the unexpectedly high uterine concentrations relative to the low serum concentration observed after vaginal administration. Hence, the vaginal route permits targeted drug delivery to the uterus, thereby maximizing the desired effects while minimizing the potential for adverse systemic effects.
first uterine pass effect vaginal progesterone, vaginal progesterone uterine tissue concentration targeted delivery, vagina to uterus drug transport mechanism, ex vivo uterine perfusion model progesterone, vaginal administration progesterone endometrial myometrial concentration, Bulletti first uterine pass effect progesterone, de Ziegler vaginal progesterone uterine delivery, luteal phase endometrial progesterone extraction higher, targeted drug delivery gynecology vaginal route, progesterone vaginal vs systemic administration uterine levels
PMID 9194669 9194669 DOI 10.1093/humrep/12.5.1073 10.1093/humrep/12.5.1073
Cite this article
Bulletti, C., de Ziegler, D., Flamigni, C., Giacomucci, E., Polli, V., Bolelli, G., & Franceschetti, F. (1997). Targeted drug delivery in gynaecology: the first uterine pass effect. Human reproduction (Oxford, England), 12(5), 1073-1079. https://doi.org/10.1093/humrep/12.5.1073
Bulletti C, de Ziegler D, Flamigni C, Giacomucci E, Polli V, Bolelli G, et al. Targeted drug delivery in gynaecology: the first uterine pass effect. Hum Reprod. 1997;12(5):1073-1079. doi:10.1093/humrep/12.5.1073
Bulletti, C., et al. "Targeted drug delivery in gynaecology: the first uterine pass effect." Human reproduction (Oxford, England), vol. 12, no. 5, 1997, pp. 1073-1079.
To verify the occurrence of preferential distribution of vaginally administered progesterone to the uterus compared with extrapelvic regions in vivo and in humans. Prospective clinical study. University medical school. PATIENT(S): Twenty postmenopausal women undergoing transabdominal hysterectomy for benign pathologies. INTERVENTION(S): Forty-five minutes before surgery, the women received a single vaginal administration of an oil-based micronized progesterone (100 mg) solution currently available on the market for IM use. During the operation, parallel blood samples were drawn from the uterine and radial arteries. MAIN OUTCOME MEASURE(S): Plasma levels of progesterone were measured by RIA. RESULT(S): Mean (+/- SD) plasma levels of progesterone were significantly higher in the uterine artery than in the radial artery (9.75 +/- 3.21 vs. 5.12 +/- 2.06 ng/mL, respectively). CONCLUSION(S): Vaginal administration allows a preferential distribution of progesterone to the uterus, which confirms the existence of the so-called "first uterine pass effect."
To determine pharmacokinetic and endometrial effects of vaginally delivered micronized P. Functionally agonadal estrogen-replacement recipients received either micronized P administered vaginally or bi-daily IM injections of P. Hourly blood samples were obtained, from baseline to 6 hours after the initial dose of P and again on simulated cycle day 21 when transvaginal ultrasound (US) measurements and tissue samples of the endometrium were performed. Blood and tissue samples were assayed for P. Endometrial histology, estrogen receptor (ER) and P receptor (PR) contents were evaluated. University of Southern California School of Medicine, Los Angeles, California. Twenty functionally agonadal and four normally ovulating women. Delivery differences were assessed by [1] endometrial P concentrations; [2] USs; [3] histologic datings; [4] ER and PR contents, and [5] serum P levels. Endometrial P concentrations were higher with vaginally administered P than endometrial concentrations observed in normal ovulatory women or women who consistently had the highest serum P after IM administration (11.50 +/- 2.60 versus 1.40 +/- 0.40 versus 0.30 +/- 0.10 ng/mg protein [36.56 +/- 8.27 versus 4.45 +/- 1.27 versus 0.95 +/- 0.32 nmol/L], respectively). After 7 days of P, no differences between either treatment regimen and control groups were detected by histologic, ultrasonographic, or immunocytochemical receptor analyses. Vaginal micronized P enhances P delivery to the uterus compared with a standard IM regimen and results in a synchronous secretory endometrial histology in agonadal women preparing for embryo donation.
InfertilityFrozen Embryo TransferPreeclampsia Risk FactorsPAPP-A and IGF-1
Mørch NF et al., 2026·Human reproduction (Oxford, England)
Are maternal concentrations of pregnancy-associated plasma protein-A (PAPP-A) and insulin-like growth factor-1 (IGF-1) influenced by the frozen embryo transfer (FET) protocol in early pregnancy? Maternal concentrations of PAPP-A and IGF-1 were significantly lower in programmed cycle (PC) FET compared to modified natural cycle (mNC) FET among ovulatory women and compared to gonadotrophin-stimulated cycle (gSC) FET in anovulatory women. PC-FET has been associated with increased risks of preeclampsia and other placenta-related complications, pointing to altered placental development. PAPP-A and IGF-1 are biochemical markers of early placental function, and reduced levels have been linked to preeclampsia and other adverse outcomes. These markers may therefore provide insight into the pathways underlying the distinct risk profile of PC-FET. STUDY DESIGN, SIZE, This is a secondary analysis from a randomized controlled trial investigating estradiol and progesterone concentrations in FET treatments. The trial was conducted at Copenhagen University Hospital-Herlev, Denmark, from April 2021 to December 2024. Biochemical analyses for PAPP-A and IGF-1 were performed on stored biobank samples from the trial. The main analyses included women with ongoing pregnancies (n = 116), while additional analyses of IGF-1 were conducted in all ovulatory women with available biobank samples (n = 193). PARTICIPANTS/MATERIALS, SETTING, Eligible participants were women aged 18-40 years with BMI ≤35 kg/m2 undergoing frozen-thawed autologous blastocyst transfer. Ovulatory women were randomized to mNC or PC, and anovulatory women to gSC or PC. Samples were collected at the following 7 timepoints on the 2nd or 3rd day of menstrual bleeding, on the day of trigger/endometrial thickness ≥7 mm, on the day of embryo transfer and by gestational ages (GA) 4 + 2, 6 + 0, 8 + 0, and 9 + 6. Data on placental weight were collected at delivery. MAIN The present analyses included women with ongoing pregnancies 43 in the ovulatory mNC group, 42 in the ovulatory PC group, 16 in the anovulatory gSC group, and 15 in the anovulatory PC group. PC had substantially lower IGF-1 concentrations from treatment initiation through GA 8 + 0 compared to both mNC and gSC. Ovulatory women treated with PC showed significantly lower PAPP-A concentrations during endometrial preparation (7.4 vs 8.7 mU/l; adjusted P = 0.02), at embryo transfer (6.7 vs 8.8 mU/l; adjusted P < 0.001), and GA 4 + 2 (7.2 vs 8.5 mU/l; adjusted P = 0.03) than women treated with mNC. Among anovulatory women, PAPP-A concentrations were also reduced during endometrial preparation (5.8 vs 9.1 mU/l; adjusted P = 0.008) in PC compared to gSC. LIMITATIONS, As this was a secondary analysis, no formal power calculation was made, and statistical power may therefore be limited. We provide evidence that PC-FET was followed by lower IGF-1 concentrations in early pregnancy and by time-dependent reductions in PAPP-A compared to mNC-FET and gSC-FET. These findings suggest alterations in early placental biology that may contribute to the adverse obstetric risk profile associated with PC-FET. Future studies should clarify whether these changes are related to the use of oral estradiol and whether alternative administration routes could modify this risk. STUDY FUNDING/COMPETING INTEREST(S): The trial was funded by Gedeon Richter Nordics AB, including analysis of biobank samples (grant numbers DK-2019-04, DK-2022-03, DK-2023-08, DK-2023-06, DK-2024-08). The trial also received one grant from the Gangsted-Rasmussen Foundation (grant number A39784) and a grant was obtained from the local research board at Copenhagen University Hospital-Herlev. The study was designed and planned independently, with no involvement from the funders in data analysis or interpretation of the results. N.F.M. has received funding for congress attendance from Gedeon Richter Nordics AB and Merck A/S, unrelated to the present work. B.N. has received grants to the institution from Merck A/S, Gedeon Richter Nordics AB, and Ferring Pharmaceuticals A/S, along with personal fees from Ferring Pharmaceuticals A/S, travel support from Gedeon Richter Nordics AB, and has participated in a data safety monitoring or advisory board for Ferring Pharmaceuticals A/S, outside of this research. M.K. has received funding from Rigshospitalets Research Board outside of this research. L.R. has received a research grant from the Novo Nordisk Foundation outside of this research. P.F.S. has received grants from Merck A/S, Gedeon Richter Nordics AB, and Ferring Pharmaceuticals A/S, travel support from Ferring Pharmaceuticals A/S, and personal fees from Novo Nordisk for webinars, outside of this study. 2020-001218-39 in EudraCT.
Are dietary patterns associated with age at menarche after accounting for BMI-for-age (BMIz) and height? We observed associations between both the Alternative Healthy Eating Index (AHEI) and the Empirical Dietary Inflammatory Pattern (EDIP) and age at menarche. Dietary patterns have been sparsely examined in relation to age at menarche and no studies have examined the association between the AHEI, a healthier diet, and EDIP, a pro-inflammatory diet, and menarche. STUDY DESIGN, SIZE, The Growing Up Today Study (GUTS) is a prospective cohort of children ages 9-14 years at study enrollment. GUTS enrolled in two waves with enrollment beginning in 1996 (GUTS1) and 2004 (GUTS2). For this analysis, GUTS1 and GUTS2 participants were followed through 2001 and 2008, respectively. PARTICIPANTS/MATERIALS, SETTING, We included 7530 participants who completed food frequency questionnaire(s) (FFQ) prior to menarche who then self-reported age at menarche during study follow-up. Cox proportional hazard models were used to calculate multivariable hazard ratios (HRs) and 95% CIs for the associations between two dietary patterns, the AHEI and EDIP, and age at menarche, with and without adjustment for time-varying BMIz and height. MAIN Six thousand nine hundred ninety-two participants (93%) reported menarche during the study period. On average, participants completed the baseline FFQ 1.75 years prior to menarche. Participants in the highest quintile of AHEI diet score (indicating a healthier diet) were 8% less likely to attain menarche within the next month compared to those in the lowest quintile (95% CI = 0.85-0.99; Ptrend = 0.03). This association remained after adjustment for BMIz and height (corresponding HR = 0.93; 95% CI = 0.86-1.00; Ptrend = 0.04). Participants in the highest quintile of the EDIP score (i.e. most inflammatory diet), were 15% more likely to attain menarche in the next month relative to those in the lowest quintile (95% CI = 1.06-1.25; Ptrend = 0.0004), and the association remained following adjustment for BMIz and height (corresponding HR = 1.15; 95% CI = 1.06-1.25; Ptrend = 0.0004). LIMITATIONS, Self-reported questionnaires are subject to some error; however, given our prospective study design it is likely this error is non-differential with respect to the outcome. Our findings of an association between both the AHEI and EDIP and age at menarche indicate that diet quality may play a role in age at menarche independent of BMI or height. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Breast Cancer Research Foundation. The GUTS is supported by the National Institutes of Health U01 HL145386. C.P.D. was supported by National Institutes of Health T32 CA094880. The authors have no conflicts of interest to disclose. N/A.