Physiologie der Lutealphase

The corpus luteum is a temporary endocrine organ that emerges from the ovulatory follicle and regresses 2 weeks after ovulation. Its primary task is the production and secretion of progesterone. Prerequisite for its normal function is a sufficient follicular phase with high estradiol levels and an adequate LH peak. Luteinization occurs by an arrest of mitosis and the transition of follicle cells to small and large luteal cells. Receptor expression alters and angiogenesis starts. The GnRH and consecutively the LH pulse frequency decreases through progesterone in the luteal phase. A new ovarian cycle evolves only after the complete elimination of the corpus luteum. Blood supply to the corpus luteum is restricted and apoptosis begins. In pregnancy the function of the corpus luteum is maintained until the placenta takes over. This luteal-placental shift occurs in the 5th week of gestation. An adequate luteal function is mirrored by sufficient estradiol and progesterone levels as surrogate parameters. The levels for progesterone should be higher than 8–10 ng/ml.     

Progesterone and estrogen secretion by puerperal human ovaries.

Plasma progesterone, estrone, and estradiol concentrations were determined in peripheral and ovarian vein samples in 9 women 20 to 30 minutes after delivery of the placenta during cesarean section. Progesterone concentrations in the ovarian vein draining the corpus luteum were significantly higher than the contralateral side or the peripheral concentration, confirming the activity of the puerperal corpus luteum. Estrone concentrations showed no significant difference between peripheral and ovarian vein samples, indicating little or no ovarian estrone secretion. The estradiol concentrations of the ovarian vein samples were significantly higher than peripheral levels. This indicates ovarian secretion of estradiol in the puerperium by areas other than the corpus luteum.     

Relation between corpus luteum function and serum prolactin concentration early in pregnancy

In 23 patients between the 6.-8. week of pregnancy the serum prolactin concentration excessively increased by bolus injection of 10 mg metoclopramide. Coincidentally the steroid secretion of the corpus luteum has been monitored by measurement the serum concentration of progesterone and estradiol. There are no changes in the corpus luteum function caused by hyperprolactinaemia under these conditions.     

Relation between corpus luteum function and serum prolactin concentration in early pregnancy

In 20 patients between the 6.-8. week of pregnancy serum prolactin concentration could be decreased successful by administration of a single dose bromocriptine. Coincidentally the steroid secretion of the corpus luteum has been monitored by measurement the serum concentration of progesterone and estradiol. There are no prolactin related changes in the corpus luteum function under these conditions.     

Human ovarian oxytocin: its source and relationship to steroid hormones

To determine the site of oxytocin in human ovaries and its relationship with ovarian steroids, oxytocin and steroid hormones were measured in ovarian tissues, ovarian vein, and peripheral blood. Corpus luteum had significantly higher oxytocin, estrone, estradiol, and progesterone concentrations than corpus albicans and ovarian stroma (p = less than 0.01 to less than 0.001). Oxytocin concentrations in corpus luteum correlated significantly with estrone, estradiol, and progesterone. Oxytocin in corpus luteum increased from 14.0 +/- 1.8 ng/gm of wet weight in early to 30.8 +/- 0.9 ng/gm in midluteal phases (p = less than 0.001). Reverse phase high pressure liquid chromatography showed similarity between oxytocin in corpus luteum and synthetic oxytocin. Ovarian vein draining corpus luteum had significantly higher plasma oxytocin (11.8 +/- 1.5 pg/ml) than those without corpus luteum (2.1 +/- 0.2 pg/ml) or in the peripheral blood (2.9 +/- 0.3 pg/ml) (p = less than 0.001). Oxytocin in corpus luteum correlated significantly with its ipsilateral ovarian vein level of oxytocin, estrone, progesterone, and 17 alpha-hydroxyprogesterone. Our findings demonstrate that oxytocin is present and probably produced in corpus luteum and secreted into its ovarian vein; it may regulate corpus luteum release of progesterone, 17 alpha-hydroxyprogesterone, and estrone.     

Influence of corpus luteum age on the steroidogenic response to exogenous human chorionic gonadotropin in normal cycling women.

OBJECTIVE: 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. STUDY DESIGN: 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. RESULTS: 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. CONCLUSION: 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.     

Luteal phase support in assisted reproductive technology

PURPOSE OF REVIEW: The purpose of this review is to discuss luteal support in assisted reproduction and to provide an evidence-based overview of the current options available. RECENT FINDINGS: The luteal phase has been found to be defective in virtually all of the stimulation protocols used for in-vitro fertilization. Common mechanisms such as supraphysiological levels of estradiol, decreased output of luteinizing hormone, inhibition of the corpus luteum and asynchronization of estradiol and progesterone may be involved in insufficient function of the corpus luteum in assisted reproductive technology. SUMMARY: Gonadotropin releasing hormone agonist undoubtedly provides benefits in stimulated cycles, however it also has adverse effects, inhibition of the corpus luteum together with supraphysiological hormonal profiles finally leading to luteal phase defects. Luteal phase support with human chorionic gonadotropin or progesterone after assisted reproduction results in increased pregnancy rates. The role of luteal phase support in these cycles has also been recently elucidated. Use of human chorionic gonadotropin for luteal phase support is associated with a marked increase in the risk of ovarian hyperstimulation syndrome, therefore progesterone is the preferred choice. Data on the benefits of estrogen supplementation are conflicting. Among the routes of progesterone administration, reductions in pregnancy rates are noted on oral administration. In spite of a lack of statistical significance, the intramuscular route seems to be more beneficial than the vaginal route when considering rates of ongoing pregnancy and live birth. Further clarification is needed on the ideal dose, the optimal route and the duration of progesterone administration in assisted reproduction.     

The ovulatory cycle. A histologic, thermal, steroid, and gonadotropin correlation

Relationships of the day of thermal nadir, day of estradiol peak, and day of LH peak to the endometrium and corpus luteum dating system were studied. Blood samples and rectal basal body temperatures were obtained daily during an ovulatory cycle from 8 healthy women who requested tubal ligation or tubal reconstruction. The tubal surgery was performed at planned intervals (1-12 days) after the luteinizing hormone (LH) peak. Endometrium and corpus luteum biopsies were taken at the same time. Daily blood samples were analyzed for plasma estrone, estradiol, progesterone, follicle stimulating hormone and LH by radioimmunoassay. The correlation of corpus luteum and endometrial dates was .97. Correlations were made between endometrial dates and time of thermal nadir (.97). Correlations were also made between corpus luteum date and time of thermal nadir (.96), time of the estradiol peak (.9) and time of the LH peak (.93). There was histologic evidence of ovulation during the 24-hour time period designated as Day 0.     

Inhibition of nitric oxide synthesis potentiates apoptosis in the rabbit corpus luteum

To determine if nitric oxide (NO) plays a role in corpus luteum (CL) physiology by affecting progesterone secretion or luteal apoptosis, an in-vitro pseudopregnant rabbit ovarian perfusion system was used to measure the effects of an inhibitor of NO synthesis, NG-nitro-L-arginine methyl ester (L-NAME), on progesterone secretion and corpus luteal apoptosis as measured by internucleosomal DNA breakdown. Pseudopregnant rabbit ovaries perfused in vitro with L-NAME did not demonstrate any significant differences compared with control ovaries in progesterone secretion. However, apoptosis, as measured by internucleosomal breakdown, was significantly increased in L-NAME-perfused CL compared with controls. While NO does not appear to directly affect progesterone secretion, there does appear to be a role for NO in CL maintenance, or a role for inhibition of NO production in CL regression.     

Luteal phase dysfunction in endometriosis: elevated progesterone levels in peripheral and ovarian veins during the follicular phase

Endometriosis has been associated with corpus luteum inadequacy and abnormalities of luteal phase progesterone (P) secretion. In this study, abnormal luteolysis, as a second factor of luteal dysfunction, was assessed in 13 women with endometriosis and 25 control patients by measurement of ovarian vein estradiol (E2) and P during the follicular phase. The results reveal that women with endometriosis have (1) significantly lower ovarian vein E2, (2) significantly higher both peripheral and ovarian vein P, and (3) threefold higher P/E2 ratios than controls during the follicular phase. These data support the concept of continued P production from an active corpus luteum well into the follicular phase of the following cycle in women with endometriosis. Failure of adequate luteolysis is a second aspect of luteal dysfunction in endometriosis and strongly supports the growing body of data confirming ovulatory asynchrony in the minimal; endometriosis infertility syndrome.     

The effect of prostaglandin F2 alpha infusion on corpus luteum function

The effect of prostaglandin (PG) F2 alpha on corpus luteum function in normal women with regular menstrual cycles was investigated. 21 women were recruited as volunteers and PGF2 alpha was infused for 8 hours (25 mgm). Infusions were given between Day 14 and 27 of the luteal phase of the cycle, with Day 14 arbitrarily considered the time of ovulation. 13 of 21 women showed a shortened luteal phase of at least 1 day or less. 1 of 2 women, given PGF2 alpha before ovulation, failed to ovulate, and 2 other patients had anovulatory cycles in the immediate postinfusion cycle. Steroid parameters (serum progesterone, urinary pregnanediol, and serum estradiol) failed to show a consistent change. Measurements of serum progesterone and estradiol during infusion showed an initial depression and subsequent elevation of steroid levels measured. It is concluded that an 8-hour infusion of PGF2 alpha in women fails to disrupt corpus luteum function.     

Benign breast disease I: hormonal investigation

One hundred eighty-four patients with benign breast disease (BBD) were studied and compared with 50 normal women. All of the women had ovulatory cycles according to a biphasic basal body temperature and a plasma prolactin in the normal range. Their corpus luteum function was evaluated by way of plasma progesterone (P) and estradiol (E2) determinations at days 5, 7, and 9 of the hyperthermic phase. In the 184 patients, plasma P over plasma E2 ratio during the luteal phase was found significantly lower than in normal women. When the patients were grouped according to type of breast lesions, it appeared that plasma P was constantly lower in all groups than in the normal women, while plasma E2 was either normal or elevated in the groups of patients with adenosis tumors and increased nodularity of both breasts. From these results it may be postulated that an imbalance in the secretion of E2 and P by the corpus luteum is a constant finding in women with benign breast disease.     

Gonadotrophin dependence of steroidogenesis by human corpora lutea of different ages during the menstrual cycle

In vitro production of progesterone and estradiol by human corpora lutea of different ages was evaluated in the presence or absence of human chorionic gonadotrophin (HCG). Progesterone production by the luteal tissue was enhanced by as little as 0.1 IU/ml HCG and maximally stimulated by approximately 10 IU/ml HCG. Estradiol production was enhanced by 100 IU/ml HCG. Under control conditions, the synthetic activities of progesterone and estradiol were highest in the luteal tissue isolated from the mid-luteal phase corpora lutea and were lowest in the late luteal phase corpora lutea. The addition of HCG (100 IU/ml) stimulated progesterone and estradiol production by early and mid-luteal phase corpora lutea, whereas HCG had no effects on steroidogenesis by late luteal phase corpora lutea. The results suggest that the age of the corpus luteum might be an important factor governing luteal cell responsiveness to gonadotrophins.     

Preovulatory determinants of human corpus luteum function.

Granulosa cells recovered from large antral follicles in pig ovaries luteinized spontaneously; bound more ¹²⁵I-labeled HCG, produced more cyclic AMP and secreted more progesterone in response to LH than cells from small and medium-sized follicles which failed to undergo morphological luteinization. Secretion of progesterone by cultures of granulosa cells, isolated from human ovarian antral follicles was found to be related to the hormonal composition of the antral fluid in follicles from which these cells were removed. Results of these in vitro studies suggest that both extent of follicular maturation and the hormonal milieu within individual follicles are determinants of the capacity of granulosa cells to luteinize and secrete progesterone. In the context of relevance of these in vitro observations to corpus luteum function in vivo, short luteal phases and inadequate progesterone secretion have been found to be associated with cycles in which mean follicular phase serum FSH levels are lower than those characteristic of cycles in which corpus luteum function is normal in women and rhesus monkeys. Collectively, these in vitro and in vivo studies are interpreted to indicate that preovulatory hormonal stimulation is a determinant of postovulatory corpus luteum function.     

Study on the direct inhibitory action of luteinizing hormone-releasing hormone on the steroidogenesis of cultured human corpus luteum cells

To evaluate the direct inhibitory action of luteinizing hormone-releasing hormone (LH-RH) on the steroidogenesis of the human ovary, the primary cultured human corpus luteum cells were investigated. The following were the effects of the addition of LH-RH: Estradiol (E2) and progesterone were produced and secreted in the cultured corpus luteum cells. In the cytoplasm of the cultured corpus luteum cells, E2 and P-antibody complexes were observed as fine granules by the immunohistochemical staining method. The progesterone production of these cells was not inhibited in the cells cultured with LH-RH 10(-8) Mol alone. The progesterone production of the cells was stimulated in the cells, cultured with gonadotropins (LH, HCG and HMG). The gonadotropin stimulated progesterone production was inhibited by LH-RH administration in the cells. In the short term incubation of the human corpus luteum cell suspension, the cyclic adenosine monophosphate (c-AMP) accumulation of the cells incubated with LH-RH alone did not change, but the gonadotropin-stimulated c-AMP accumulation of the corpus luteum cells was significantly inhibited by LH-RH. Concerning these results, it is concluded that LH-RH inhibits the gonadotropin stimulated progesterone production directly in vitro. It is suggested that the mechanisms of these inhibitory actions of the LH-RH are related to the gonadotropin receptor-adenyl cyclase systems, c-AMP metabolizing enzyme and/or progesterone metabolizing enzyme.     

Impact of ovarian stimulation on corpus luteum function and embryonic implantation

The luteal phase has been found to be defective in virtually all the stimulation protocols used in in-vitro fertilization (IVF), indicating that common mechanisms might be involved despite the use of different drugs. A normal luteal phase is characterised by a normal hormonal environment, normal progesterone secretion by the corpus luteum and adequate endometrial secretory transformation. Luteinizing hormone supports the corpus luteum and luteal luteinizing hormone (LH) levels have been found to be reduced in human menopausal gonadotrophin (HMG), gonadotrophin-releasing hormone (GnRH)-agonist/HMG and GnRH-antagonist/HMG protocols, probably leading to an insufficient corpus luteum function. Supraphysiological steroid serum concentrations routinely observed in stimulated cycles may adversely affect LH secretion and induce a luteal-phase defect. In turn, these high steroid serum concentrations may advance early luteal-phase endometrial development leading to embryo-endometrial asynchrony and decreased pregnancy rates in IVF cycles.     

Effects of low-dose human chorionic gonadotropin on corpus luteum function after embryo transfer

This paper reports the effect of low-dose human chorionic gonadotropin (hCG) on the levels of serum hCG, progesterone, and estradiol, luteal-phase length, and conception in 20 patients undergoing in vitro fertilization and embryo transfer (IVF-ET). Alternate patients in a group of 20 received 1000 IU hCG on the day of embryo transfer and 3 days after. Six and 9 days from embryo transfer 2000 IU hCG was given. The remaining patients served as controls. No patients in the treated group and four in the control group became pregnant. The endocrine profiles with respect to hCG, progesterone, and estradiol levels were similar in the treated patients compared with pregnant patients in the control group. Treated patients had significantly longer (18.0±1.1 days) luteal phases compared with nonpregnant patients in the control group (12.5±1.2 days), indicating that low-dose hCG prolonged the life of the corpus luteum. It was concluded that while the administration of low-dose hCG prolonged the life of the corpus luteum, it did not apparently improve the conception rate.     

The corpus luteum: determinants of progesterone secretion in the normal menstrual cycle

Fourteen normal volunteers were studied during one menstrual cycle. Follicular development, the luteinizing hormone (LH) surge, and the relationship between LH and progesterone secretion in the luteal phase were studied to determine the factors that control corpus luteum function. Follicular development was assessed by measuring follicle size and daily estradiol (E2) levels; the LH surge was quantified by determining the area under the curve. Although there was a significant positive correlation between mean follicle diameter and E2, these same parameters did not correlate with postovulatory progesterone secretion; nor did the LH surge correlate with progesterone secretion. A decrease in LH pulse frequency occurred in moving from the follicular to the luteal phase. There was a trend toward an increase in the late luteal LH pulse frequency compared with the midluteal phase, but this was not significant. Progesterone was secreted in an intermittent (pulsatile) fashion in the midluteal and late luteal phases. The general decrease in progesterone in the latter days of the menstrual cycle appears to be due to a decrease in the progesterone pulse amplitude. A significant correlation between LH and progesterone was present when the data were "smoothed"; however, there was not a significant synchrony for LH and progesterone pulses for most of the subjects when the initial data were analyzed by objective criteria. Progesterone secretion in the luteal phase is quite complex and leads to highly variable serum levels of progesterone when samples are obtained at random from normal women.     

Early and late hormonal changes following progesterone injection to patients with secondary amenorrhea.

In humans, progesterone (Po) administration has been shown capable of eliciting luteinizing hormone (LH) and prolactin surges in a good estrogenic milieu, but whether such changes induce corpus luteum function still remains controversial. We therefore proposed to explore further the second hypothesis in a placebo-controlled type of study. In patients with secondary amenorrhea and low circulating estradiol (E2) levels with or without ovaries, a 50-mg progesterone injection induced only a short and transient rise in plasma Po levels. On the other hand, a similar injection to patients with mid-to late follicular levels of circulating E2 and intact ovaries induced a surge of plasma LH and prolactin which was followed by a sustained elevation in plasma Po. Furthermore, a rise in basal body temperature accompanied by evidence of secretory endometrium was also observed in these patients. It is concluded that, in a proper endocrine milieu, progesterone administration may induce luteinization in human subjects.     

Endometrial estradiol and progesterone receptors in patients with luteal phase defects and endometriosis

Endometrial cytosol estrogen receptors (ERs) and progesterone receptors (PgRs) were quantitated in postovulatory endometrial biopsy samples of patients with luteal phase defect (LPD), those with endometriosis, and normal control subjects. Serum levels of estradiol (E2) and progesterone (P), obtained on the day of the biopsy, were also measured. No significant differences among endometrial ER, PgR, serum E2, and P levels were detected between the patients with endometriosis and normal control subjects. Although ER concentrations in the luteal defect group did not differ from those of control subjects, the PgR levels in day 20 to 23 endometrium were significantly higher. Mean serum E2 and P levels in the group with luteal insufficiency were significantly lower than those of the control subjects. Our data suggest that in patients with LPD the increase in PgR levels during the midluteal days is compatible with a relative deficiency of P secretion by the corpus luteum.