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Graafian follicles, dissected intact from the rabbit ovary and incubated for 40 minutes with luteinizing hormone, developed into corpora lutea when autotransplanted under the kidney capsule. Follicles incubated with follicle-stimulating hormone or without hormone degenerated and failed to luteinize. Direct exposure of the mammalian follicle to luteinizing hormone initiates luteinization and formation of the corpus luteum.
In normal albino rats with a 4-day estrous cycle, the activity of ovarian ornithine decarboxylase undergoes a transitory rise on the evening of proestrus and only at that time. The response could be elicited by the administration of either luteinizing hormone or human chorionic gonadotrophin. When antiserum to luteinizing hormone was injected at 2 p.m. on the day of proestrus, the induction of ornithine decarboxylase was blocked, an indication that the enzyme is under luteinizing hormone control. The strategic positioning of the induction of ornithine decarboxylase between the normal release of luteinizing hormone and ovulation impties that putrescine is associated with the ovulatory process, and opens a new avenue of research on the control of ovulation.
PURPOSE: To investigate the relation between plasma concentrations of lutein and zeaxanthin and age-related macular degeneration in a group of elderly men and women. METHODS: The Wisconsin Age-Related Maculopathy Grading System was used to grade features of early and late macular degeneration in 380 men and women, aged 66 to 75 years, from Sheffield, United Kingdom. Fasting blood samples were taken to assess plasma concentrations of lutein and zeaxanthin. RESULTS: Risk of age-related macular degeneration (early or late) was significantly higher in people with lower plasma concentrations of zeaxanthin. Compared with those whose plasma concentrations of zeaxanthin were in the highest third of the distribution, people whose plasma concentration was in the lowest third had an odds ratio for risk of age-related macular degeneration of 2.0 (95% confidence interval [CI] 1.0-4.1), after adjustment for age and other risk factors. Risk of age-related macular degeneration was increased in people with the lowest plasma concentrations of lutein plus zeaxanthin (odds ratio [OR] 1.9, 95% CI 0.9-3.5) and in those with the lowest concentrations of lutein (OR 1.7, 95% CI 0.9-3.3), but neither of these relations was statistically significant. CONCLUSIONS: These findings provide support for the view that zeaxanthin may protect against age-related macular degeneration.
In association with luteinization, LH induces a decrease in the content of receptors for FSH and LH and an increase in that for PRL. To elucidate if the mechanism by which LH regulates its own receptors involved occupancy of sites and/or loss of receptors the effects of a luteinizing dose of LH were examined in the preovulatory follicles of immature hypophysectomized rats primed with estradiol and FSH. The measurable LH receptor content declined by 82% 24 h after LH administration. Serum concentration of the hormone declined by 24 h to 1.4% of the concentration measured 2 h after LH administration. Administration of iodinated LH to demonstrate occupancy of sites in vivo, resulted in a decline in the amount of hormone bound in vivo, over a period of time. This decline in occupancy paralleled the decrease in the number of available sites as measured in vitro. Furthermore, a large dose of highly purified hFSH administered in lieu of LH induced luteinization and an associated loss of gonadotropin receptors. These results indicate that luteinizing doses of LH and FSH induce a loss in gonadotropin receptors by mechanisms other than occupancy.
The time- and dose-dependent effects of bovine FSH-suppressing protein (FSP)/follistatin and human recombinant activin A (hr-Act) on oxytocin (OT) and progesterone (P) production, markers of luteinization, were studied in mature and immature bovine granulosa cells (GC), using three forms of FSP (31, 35, and 39 kDa) and a FSP pool consisting of 35, 39, and 45 kDa forms. FSP alone had no detectable effect on OT and P production when added to cultures of fully differentiated bovine GC. On the other hand, all FSP forms (10-100 ng/ml) enhanced and prolonged OT and P production of immature GC induced by bovine LH (10 ng/ml). Overall, 35 kDa FSP was more effective than the other forms tested. Hr-Act alone had a dose-dependent inhibitory effect on OT and P production on LH-stimulated immature GC. All four forms of FSP (30 or 100 ng/ml) added to cultures treated with hr-Act, reversed the inhibitory effect of hr-Act, with a significant increase (25%) above control levels using the 35 and 39 kDa FSP forms. In conclusion, FSP enhanced and prolonged the luteinization process, as indicated by OT and P production induced in immature GC by bovine LH, and was able to antagonize the inhibitory effect of hr-Act in this system. These studies suggest a physiological role for activin and FSP, as modulators of folliculogenesis and luteinization in the ovary. We propose that activin and FSP act in an autocrine fashion on GC in the ovarian follicle to regulate folliculogenesis and luteinization.
CONTEXT: Polycystic ovary syndrome (PCOS) is a reproductive disorder of ovarian hyperandrogenism and insulin resistance characterized by abnormal luteinization of small follicles. After exposure to GnRH analog/FSH stimulation for in vitro fertilization (IVF), however, it is unclear whether such PCOS follicles remain abnormally luteinized during the resumption of oocyte maturation in vivo. OBJECTIVE: The aim of this study was to determine whether PCOS follicles exposed to GnRH analog/FSH stimulation for IVF show abnormal luteinization. DESIGN: This study was a prospective cohort. SETTING: The setting was an institutional practice. PATIENTS: Eleven PCOS and 30 normoandrogenic ovulatory women were included. INTERVENTION(S): All subjects received GnRH analog/FSH therapy after basal serum hormone determinations. MAIN OUTCOME MEASURE(S): Follicle fluid aspirated at oocyte retrieval from the first follicle of each ovary was assayed for gonadotropins, steroids, insulin, and glucose. LH receptor mRNA expression was determined in granulosa cells of the same follicle. RESULTS: In PCOS patients with basal hyperandrogenemia and hyperinsulinemia, total oocyte number was increased and follicle diameter was decreased, despite normal maximal serum estradiol levels. Within PCOS follicles, progesterone levels were reduced (P < 0.01), despite comparable bioactive LH and insulin levels and granulosa cell LH receptor mRNA expression; estradiol levels were normal, despite diminished FSH availability (P < 0.004). Elevated androstenedione (P < 0.01), testosterone (P < 0.001), and glucose (P < 0.01) levels also occurred. In PCOS follicles containing mature oocytes, however, elevated androgen levels were accompanied by both normal progesterone concentrations and a normal inverse relationship between glucose depletion and lactate accumulation. CONCLUSION: Hyperandrogenic follicles with mature oocytes from PCOS women receiving GnRH analog/recombinant human FSH therapy for IVF show sufficient glucose utilization for normal luteinization.
Despite having amenorrhea and markedly elevated serum gonadotropin levels, some women with karyotypically normal spontaneous premature ovarian failure, nevertheless, have ovarian follicles that function intermittently. Graafian follicles capable of responding to these high FSH levels are faced with high serum LH levels as well, which might induce inappropriate luteinization and prevent normal follicle function. We examined this possibility using weekly blood sampling and sonography in 65 patients. Nearly 50% of our patients demonstrated ovarian follicle function [serum estradiol, > 183 pmol/L (50 pg/mL)] during a median of 4 months of observation (range, 2-6 months). However, during this observation, only 16% achieved an ovulatory serum progesterone level [> 9.5 nmol/L (3.0 ng/mL)]. We imaged an antral follicle by sonography in over 40% of patients (27 of 65), and serum estradiol was significantly greater when an antral follicle was present. The follicles in these patients were not functioning normally, however. In contrast to normal women, patients with ovarian failure had poor correlation between follicle diameter and serum estradiol. We biopsied these antral follicles in 6 patients and found luteinized Graafian follicles in all cases. Therefore, luteinized Graafian follicles account for at least 60% of the antral structures imaged (95% confidence limit). Thus, inappropriate luteinization of Graafian follicles appears to be a major pathophysiological mechanism in patients with karyotypically normal spontaneous premature ovarian failure.
Luteinization of follicular granulosa cells leads to an increase in progesterone secretion that is regulated by luteinizing hormone (LH). LH acts mainly by elevating intracellular cyclic 3',5'-adenosine monophosphate (cAMP) and activating cAMP-dependent protein kinase (PKA). In this study, we have examined the role of PKA in relation to progesterone output by luteinizing human granulosa cells. Human granulosa cells were obtained by percoll gradient centrifugation of follicular aspirates of patients undergoing oocyte retrieval for assisted conception. Cells were cultured in serum-supplemented medium for up to 3 days in the presence and/or absence of human (h)LH and other cAMP-elevating agents. Spent medium was assayed for cAMP and progesterone content by specific RIA. Cell lysates were collected and assessed for PKA regulatory (R)IIalpha/catalytic (C)alpha expression by Western blotting. Although basal progesterone secretion increased progressively throughout culture, cAMP levels remained unchanged. Under basal conditions, PKA RIIalpha/Calpha expression appeared to increase throughout the 3-day culture period. In the presence of hLH and other cAMP-elevating agents, progesterone secretion increased in a dose-dependent manner coincident with an increase in cAMP. However, despite the increase in both progesterone secretion and cAMP accumulation, there was a dose-dependent decrease in both PKA RIIalpha and Calpha expression. Thus, data presented in this study show that increases in progesterone secretion in luteinizing human granulosa cells can be dissociated from increases in PKA expression. This notion implies that progesterone secretion may be regulated by PKA-dependent as well as PKA-independent mechanisms.
We have investigated the hormone profiles and the relationship between serum testosterone and luteinizing hormone in men with long-standing acne vulgaris. In the controls, age correlated with the free androgen index and with serum dehydroepiandrosterone-sulphate, so for the purposes of comparison 33 men with acne vulgaris were age-matched against 33 controls. Compared with controls, the acne patients had higher medians of serum androstenedione, testosterone and free androgen index. In both groups there was a significant correlation between testosterone and luteinizing hormone levels. For a given level of luteinizing hormone the patients with acne tended to have higher levels of serum testosterone than normal controls. These results indicate that in this group of men with long-standing acne there was either increased responsiveness of the target organ to luteinizing hormone or there was an increased amount of androgen-secreting tissue.
The effects of suckling on secretion of luteinizing hormone, cortisol and transcortin were investigated in anovulatory postpartum cows. On d 35 postpartum, calves were separated from 12 cows to prevent suckling and eight calves continued to suckle their dams ad libitum. Between 35 and 41 d postpartum, samples of jugular blood were collected every 15 min for two periods of 6 h/d. In non-suckled cows, frequency of pulses and basal luteinizing hormone increased but amplitude of pulses did not change. Concentrations of total cortisol in serum of cows were not altered during 3 d after weaning calves and did not differ among intervals before, during and after a suckling event. Affinity of transcortin for cortisol was not affected by postpartum interval or treatment. Capacity of transcortin to bind cortisol tended to increase after weaning. We found no evidence to support the hypothesis that suckling reduces binding capacity of transcortin or increases unbound cortisol. Differences in preovulatory secretion of luteinizing hormone between suckled and non-suckled cows could not be accounted for by differences in secretion of cortisol. In beef cows that are fed to satisfy requirements for energy and have average body condition, we conclude that negative modulation of luteinizing hormone by suckling is not mediated by cortisol.
Seven Holstein heifers were subjected to 15-min periods of stress two times per day for 3.5 days during the follicular phase of the estrous cycle. In two of seven trials, stressed animals had no preovulatory surge in luteinizing hormone whereas in control experiments all seven had surges. Peak luteinizing hormone concentrations in the five animals having surges, as well as basal luteinizing hormone concentrations in all seven animals, were unaffected by treatment. Estrous behavior also was unaffected by stress, and all animals displayed estrus during treatment. The 24-h pattern of corticosteroids of plasma was unaffected by treatment; however, there was a significant brief elevation in corticosteroids following stress. These results suggest that brief stress can disrupt the preovulatory luteinizing hormone surge in the cow and that this effect may have significant implications for dairy management.
Thirteen lactating Holstein cows were assigned randomly to either a control or beta-carotene (600 mg/d) treatment group to determine the effect of long-term beta-carotene supplementation on releasable luteinizing hormone in response to gonadotropin-releasing hormone challenge. The experimental period was 28 wk. Milking was terminated at wk 16, ovariectomy performed at wk 20, and response to gonadotropin-releasing hormone determined at wk 27. Serum beta-carotene concentrations reflected dietary intake and were higher in the cows fed beta-carotene after 2 wk of supplementation and remained higher for the duration of the trial. Feeding supplemental beta-carotene had no effect on circulating progesterone concentration, corpora lutea size or corpora lutea progesterone concentration, or basal concentrations of luteinizing hormone, frequency, and amplitude of luteinizing hormone pulses, or the release of luteinizing hormone in response to gonadotropin-releasing hormone. Thus, pituitary responsiveness to exogenous gonadotropin-releasing hormone was not affected by feeding supplemental beta-carotene.
We examined the effects of all-trans retinoic acid (ATRA) and lutein (a nonprovitamin A carotenoid), on apoptosis and chemosensitivity in primary normal human mammary epithelial cells, SV40 transformed mammary cells, and MCF-7 human mammary carcinoma cells. ATRA and lutein selectively induced apoptosis in transformed but not normal human mammary cells. In addition, both compounds protected normal cells, but not transformed cells, from apoptosis induced by the chemotherapy agents etoposide and cisplatin. Furthermore, lutein and ATRA selectively increased the ratio of Bcl-xL:Bax protein expression in normal cells but not transformed mammary cells, suggesting a possible mechanism for selective modulation of apoptosis. The differential effects of lutein and ATRA on apoptotic pathways in normal versus transformed mammary epithelial cells may have important implications for chemoprevention and therapy.
The steroidogenic activity of cumulus oophorus granulosa cells obtained from unstimulated rabbits in estrus has been investigated at closely timed intervals in short-term cultures. The presence of viable, structurally well preserved oocytes and the addition of large follicle follicular fluid had no apparent inhibitory effect on progesterone or estrogen synthesis and secretion. Progesterone secretion was especially stimulated by the addition of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) to the culture medium. A similar increment was also seen, although inconsistently, for estrogen secretion. Ultrastructural evidence of luteinization was demonstrated by quantitative morphometric techniques in control cultures as early as 6 hours after explantation and was shown to relate well to biochemical luteinization. It is suggested that the main modifications in cytoplasmic organelles concomitant with luteinization may be represented only by volume and surface changes rather than by alterations in morphology. Therefore, such changes need to be assessed quantitatively. Oocytes exhibited isolated maturative changes almost exclusively in FSH-LH cultures, such as cortical granule synthesis, resumption of meiosis, polar body extrusion, and two-cell parthenogenetic cleavage. It is suggested that cumulus granulosa cells may play a significant role in the resumption of "spontaneous" maturation in oocytes after their release in vitro from their follicles. Characteristic, thin-walled vesicles, either isolated or in rosette-like formation with cumulus granulosa cells, were described. A possible common nature was suggested for these vesicles and the so-called "Call-Exner bodies."
A study was initiated to evaluate the prevalence of the luteinized unruptured follicle (LUF) syndrome in a group of 355 women with infertility. The diagnosis was established by carefully observing daily sonograms along with measuring estradiol, progesterone, and luteinizing hormone (LH) levels. Two distinct types of LUF syndrome were identified: mature follicle LUF, in which release of an ovum was not demonstrated after a follicle attained maturity (serum estradiol reached 200 pg/mL while serum progesterone remained less than 2.5 ng/mL), versus premature luteinization LUF, where the serum progesterone increased above 2.5 ng/mL before follicular maturation was attained. The use of either hCG alone or hCG in combination with hMG in a single injection at the time of follicular maturation successfully corrected mature follicle LUF in 21 of 46 patients (46%), whereas ovulation-inducing drugs plus hCG or hCG and hMG corrected LUF in 24 of 25 patients (96%). Clomiphene citrate proved inferior to hMG in that it corrected LUF in 3 of 25 patients (12%) versus 12 of 22 patients (95%) who had undergone hMG therapy. Thus, hMG-hCG therapy is the most efficacious for mature follicle LUF, but because release can occur spontaneously on occasion by an appropriately timed single gonadotropin injection, one could offer the less costly options first. For premature luteinization, speeding up follicular maturation with gonadotropin therapy is effective. Upon failure of this technique, the more costly endogenous gonadotropin suppression followed by hMG can be employed.
The time-course of appearance of five carotenoids in chylomicrons and their distribution pattern were studied following ingestion of a single dose of Betatene, a natural carotenoid source composed of 0.5% lutein, 0.75% zeaxanthin, 3.6% alpha-carotene, 70.3% all-trans beta-carotene, 22.7% beta-carotene cis isomers, 2.1% unidentified carotenoids and no lycopene. Lutein, zeaxanthin, alpha-carotene and all-trans beta-carotene but not lycopene levels in chylomicrons increased after Betatene ingestion with a maximum at 9 h and a distinct decline from 9 to 12 h. However, the carotenoid pattern in the chylomicron fraction did not match the pattern in Betatene, with a 14-fold and 4-fold higher level of lutein and zeaxanthin, respectively, compared to their content in Betatene. The contribution of alpha-carotene to the carotenoid composition in chylomicrons reflected its content in Betatene, whereas the relative amount of all-trans beta-carotene was substantially lower than in Betatene. Thus, in the presence of high amounts of beta-carotene, there is a preferential uptake of the xanthophylls lutein and zeaxanthin as compared to all-trans beta-carotene from the intestinal lumen into chylomicrons.
The objective was to evaluate the molecular ratio between the serum levels of progesterone (P) and estradiol (E2) and to determine it's effect on the in vitro fertilization performance. Sixty two couples were studied, the molecular P:E2 ratio was established the day of human chorionic gonadotropin (hCG) injection. The mean serum P concentration the day of hCG administration 1.45 +/- 0.50 ng/mL, while the mean P:E2 ratio was 0.63 +/- 0. Pregnancies were observed since molecular ration of 0.22, no pregnancies were obtained if the molecular ratio was > 1.02. No significant difference was detected in the fertilization and pregnancy rates in the patients who have or not premature luteinization. The implantation rate was low in patients with premature luteinization, however, there was not significant difference with patients without premature luteinization. In conclusion, the P:E2 ratio surrounding 1.0 is desirable to obtain adequate results in in vitro fertilization programs. In this work as others, the premature luteinization do not have effect in the reproductive results.
The ovarian corpus luteum plays a critical role in reproduction being the primary source of circulating progesterone. After ovulation the corpus luteum is build by avascular granulosa lutein cells through rapid vascularization regulated by gonadotropic hormones. The present study was performed to investigate whether this process might be influenced by the human chorionic gonadotropin (hCG)-dependent expression of different tumor suppressor genes and hypoxia dependent transcription factors. RNA was isolated from cultured granulosa lutein cells, transcribed into cDNA, and the transcript level of following genes were determined: RB-1, VHL, NF-1, NF-2, Wt-1, p53, APC, and hypoxia inducible factor-1 (HIF-1), -2, and -3alpha. Additionally, the influence of hCG on the expression of VHL, p53, and HIf2alpha were investigated. We demonstrate that in human granulosa lutein cells the tumor suppressor genes RB-1, VHL, NF-1, NF-2, Wt-1, p53, and APC and the hypoxia dependent transcription factors HIF-1alpha, -2alpha, and -3alpha are expressed. In addition, we showed that hCG regulates the expression of p53, VHL, and HIF-2alpha. Our results indicate that hCG may determine the growth and development of the corpus luteum by mediating hypoxic and apoptotic pathways in human granulosa lutein cells.