Wulff, C., Dickson, S. E., Duncan, W. C., & Fraser, H. M. (2001). Angiogenesis in the human corpus luteum: simulated early pregnancy by HCG treatment is associated with both angiogenesis and vessel stabilization. Human reproduction (Oxford, England), 16(12), 2515-2524. https://doi.org/10.1093/humrep/16.12.2515
Wulff C, Dickson SE, Duncan WC, Fraser HM. Angiogenesis in the human corpus luteum: simulated early pregnancy by HCG treatment is associated with both angiogenesis and vessel stabilization. Hum Reprod. 2001;16(12):2515-2524. doi:10.1093/humrep/16.12.2515
Wulff, Christine, et al. "Angiogenesis in the human corpus luteum: simulated early pregnancy by HCG treatment is associated with both angiogenesis and vessel stabilization." Human reproduction (Oxford, England), vol. 16, no. 12, 2001, pp. 2515-2524.
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From Tommy’s National Centre for Miscarriage Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham (A.C., A.J.D., V.C., H.H., L.J.M., I.D.G., H.W., A.K.E., T.R., C....05y3qh794
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Abstract
Background
This study examined changes in the luteal vasculature throughout the menstrual cycle and during simulated pregnancy with human chorionic gonadotrophin (HCG) in the human.
Methods
Endothelial cell and pericyte area were assessed by quantitative immunocytochemistry for CD34 and alpha-smooth muscle actin respectively, taking into consideration the dynamics of lutein cell hypertrophy and atrophy throughout the cycle and after HCG treatment. Endothelial cell proliferation was detected by Ki-67/CD34 dual staining and a proliferation index was obtained. The molecular regulation of angiogenesis was studied by examining changes in vascular endothelial growth factor (VEGF) immunostaining.
Results
The early luteal phase is associated with intense angiogenesis, as indicated by high endothelial cell proliferation, and by the mid-luteal phase a mature vasculature was apparent, as shown by maximal endothelial cell and pericyte areas. During the late luteal phase, decreased endothelial proliferation, endothelial cell and pericyte area indicated vascular regression. HCG treatment induced a second burst of total and endothelial cell proliferation and a concomitant increase in endothelial cell and pericyte areas. VEGF protein was expressed throughout the luteal phase and a significant increase was found after HCG treatment.
Conclusion
Luteal rescue with HCG is associated with a second wave of angiogenesis and vascular stabilization.
Coomarasamy A et al., 2019·N Engl J Med·Free to read
Bleeding in early pregnancy is strongly associated with pregnancy loss. Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone therapy may improve pregnancy outcomes in women who have bleeding in early pregnancy. We conducted a multicenter, randomized, double-blind, placebo-controlled trial to evaluate progesterone, as compared with placebo, in women with vaginal bleeding in early pregnancy. Women were randomly assigned to receive vaginal suppositories containing either 400 mg of progesterone or matching placebo twice daily, from the time at which they presented with bleeding through 16 weeks of gestation. The primary outcome was the birth of a live-born baby after at least 34 weeks of gestation. The primary analysis was performed in all participants for whom data on the primary outcome were available. A sensitivity analysis of the primary outcome that included all the participants was performed with the use of multiple imputation to account for missing data. A total of 4153 women, recruited at 48 hospitals in the United Kingdom, were randomly assigned to receive progesterone (2079 women) or placebo (2074 women). The percentage of women with available data for the primary outcome was 97% (4038 of 4153 women). The incidence of live births after at least 34 weeks of gestation was 75% (1513 of 2025 women) in the progesterone group and 72% (1459 of 2013 women) in the placebo group (relative rate, 1.03; 95% confidence interval [CI], 1.00 to 1.07; P = 0.08). The sensitivity analysis, in which missing primary outcome data were imputed, resulted in a similar finding (relative rate, 1.03; 95% CI, 1.00 to 1.07; P = 0.08). The incidence of adverse events did not differ significantly between the groups. Among women with bleeding in early pregnancy, progesterone therapy administered during the first trimester did not result in a significantly higher incidence of live births than placebo. (Funded by the United Kingdom National Institute for Health Research Health Technology Assessment program; PRISM Current Controlled Trials number, ISRCTN14163439.).
Recent evidence suggests that human chorionic gonadotropin (hCG), in addition to its well-known endocrine effects on the corpus luteum, may act as a growth and differentiation factor during pregnancy. According to experimental results, its mode of action may be divided into three sequential phases. During the first phase, which begins at the blastocyst stage and lasts until the occurrence in the serum, hCG acts preferentially in a juxtacrine manner. We have used an intrauterine microdialysis system developed in our laboratory to administer low concentrations of hCG to the endometrium of women in the luteal phase of the menstrual cycle. HCG administration provoked profound effects on paracrine parameters of differentiation (IGFBP-1, prolactin) and implantation (LIF, M-CSF). VEGF, a cytokine important for neoangiogenesis, was significantly stimulated by hCG (P < .01), suggesting a role for hCG in the control of endometrial vascularization and placentation. The investigation of endometrial parameters of tissue remodeling revealed a significant increase of MMP-9 (P < .05) but not of TIMP-1 following hCG infusion. The second, endocrine, phase of hCG action is marked by the appearance of hCG in the maternal serum. Rising systemic hCG levels cause a very rapid elevation of serum progesterone reflecting the rescue of the corpus luteum. Other endocrine functions of hCG include its intrinsic thyrotropic activity as well as modulation of fetal testicular, ovarian, and adrenal function. The third phase may be characterized by the expression of full-length hCG/LH receptors on the trophoblasts themselves. Before the ninth week of gestation, human villous trophoblasts express a truncated hCG/LH receptor isoform (50 kDa) and are probably not responsive to hCG. Later, the expression pattern is switched to the full-length receptor (80 kDa), allowing hCG also to modulate the differentiation of the trophoblasts themselves. A special feature is the self-regulation of hCG biosynthesis that may in part explain the unique secretion profile of the hormone with peak levels during the first trimester followed by a rapid decline after the tenth week of gestation. In summary, hCG seems to have a variety of local and systemic functions in and outside the embryo-endometrial microenvironment.
The null hypothesis of this study is that the patterns of steroid secretion exhibited by the human corpus luteum in response to exogenous human chorionic gonadotropin stimulation are independent of corpus luteum age at the time of treatment. Twenty-five normally cycling women in whom the midcycle urinary luteinizing hormone surge (luteal day 0) was identified and from whom blood samples were obtained daily from cycle day 11 until menses were prospectively randomized to receive no treatment (group I, n = 5) or exogenous human chorionic gonadotropin 5000 IU administered intramuscularly on luteal day 0 (group II, n = 5), +4 (group III, n = 5), +8 (group IV, n = 5), or +12 (group V, n = 5). Serum concentrations of estrone, estradiol, progesterone, 17-hydroxyprogesterone, and androstenedione were measured by specific radioimmunoassays in all subjects; serum human chorionic gonadotropin concentrations were determined by immunoradiometric assay in treated subjects. Serum human chorionic gonadotropin levels (mean +/- SEM) were virtually identical among treatment groups (p greater than 0.05). Luteal phase duration (mean +/- SEM) was prolonged (p less than 0.05) only in group V (18.4 +/- 0.5 days) compared with untreated subjects (group I 13.8 +/- 0.7 days). In all groups estrone and 17-hydroxyprogesterone concentrations closely paralleled those of estradiol and progesterone, respectively. Steroid data and progesterone/estradiol ratios (mean +/- SEM) in groups I and II were indistinguishable and were combined (control, n = 10). Group III subjects exhibited patterns of steroid secretion similar to groups I and II, although progesterone was moderately increased after human chorionic gonadotropin treatment. In groups IV and V, progesterone increased (p less than 0.05) 1 day after human chorionic gonadotropin and remained elevated for 5 to 6 days; a 4-day rise (p less than 0.05) in estradiol began 3 days after treatment, and androstenedione rose modestly in parallel. Progesterone/estradiol ratios in groups III through V increased (p less than 0.05) approximately twofold after human chorionic gonadotropin treatment and remained elevated for 4 to 5 days. The human corpus luteum exhibits distinct age-dependent patterns of steroid secretion in response to exogenous human chorionic gonadotropin stimulation, an observation that may have clinical implications regarding the empirical use of exogenous human chorionic gonadotropin in support of luteal function.
Human chorionic gonadotropin (hCG) is widely used as a surrogate to luteinizing hormone (LH) to trigger ovulation in controlled ovarian hyperstimulation (COH). Yet this molecule may exert direct effects on the endometrium. These effects, not mediated by ovarian hormones, are probably a consequence of stimulation of endometrial hCG/LH receptors. Because the half-life of hCG differs markedly from that of LH, possible pharmacological effects of hCG on the endometrium could alter endometrial receptivity in COH. Arguments supporting a clinical action of gonadotropins, and hCG in particular, on the endometrium abound. Notably, evidence has been reported of decidualization of stromal cells of the human endometrium in vitro as a result of exposure to gonadotropins, including hCG. The present article discusses, from a clinical standpoint, the main basis supporting the hypothesis that hCG administration as commonly used in infertility treatments may exert direct effects in vivo on endometrial histology and partake in endometrial transformations of the luteal phase. Preliminary results suggest that endometrial effects of hCG exist in vivo and should be taken into account when assessing the endometrial effects of hormones.
To characterize the variability of hormonal profiles during the luteal phase in normal cycles. Observational study. Not applicable. PATIENT(S): Ninety-nine women contributing 266 menstrual cycles. INTERVENTION(S): The women collected first morning urine samples that were analyzed for estrone-3-glucuronide, pregnanediol-3-alpha-glucuronide (PDG), FSH, and LH. The women had serum P tests (twice per cycle) and underwent ultrasonography to identify the day of ovulation. MAIN OUTCOME MEASURE(S): The luteal phase was divided into three parts: the early luteal phase with increasing PDG (luteinization), the midluteal phase with PDG ≥10 μg/mg Cr (progestation), and the late luteal phase (luteolysis) when PDG fell below 10 μg/mg Cr. RESULT(S): Long luteal phases begin with long luteinization processes. The early luteal phase is marked by low PDG and high LH levels. Long luteinization phases were correlated with low E1G and low PDG levels at day 3. The length of the early luteal phase is highly variable between cycles of the same woman. The duration and hormonal levels during the rest of the luteal phase were less correlated with other characteristics of the cycle. CONCLUSION(S): The study showed the presence of a prolonged pituitary activity during the luteinization process, which seems to be modulated by an interaction between P and LH. This supports a luteal phase model with three distinct processes: the first is a modulated luteinization process, whereas the second and the third are relatively less modulated processes of progestation and luteolysis.
Reproductive Endocrinology › Luteal Phase › Corpus Luteum Function · Menstrual Cycle › Cycle Physiology › Luteal Phase · Pregnancy › Early Pregnancy › Progesterone Support
W Colin Duncan
PMID 11726568 11726568 DOI 10.1093/humrep/16.12.2515 10.1093/humrep/16.12.2515 Wulff et al. 2001, Wulff 2001
Cite this article
Wulff, C., Dickson, S. E., Duncan, W. C., & Fraser, H. M. (2001). Angiogenesis in the human corpus luteum: simulated early pregnancy by HCG treatment is associated with both angiogenesis and vessel stabilization. Human reproduction (Oxford, England), 16(12), 2515-2524. https://doi.org/10.1093/humrep/16.12.2515
Wulff C, Dickson SE, Duncan WC, Fraser HM. Angiogenesis in the human corpus luteum: simulated early pregnancy by HCG treatment is associated with both angiogenesis and vessel stabilization. Hum Reprod. 2001;16(12):2515-2524. doi:10.1093/humrep/16.12.2515
Wulff, Christine, et al. "Angiogenesis in the human corpus luteum: simulated early pregnancy by HCG treatment is associated with both angiogenesis and vessel stabilization." Human reproduction (Oxford, England), vol. 16, no. 12, 2001, pp. 2515-2524.
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