Corpus Luteum Insufficiency Research Articles

Behandlung der Risikoschwangerschaft mit Gravibinon®

A retrospective study was carried out in 47 patients 22 to 43 years of age, with a mean of 32.3 years, with a total of 51 high-risk pregnancies. The patients were treated with Gravibinon starting at the 5th week of pregnancy, and continuing up to the 20th. Indications for treatment were low progesterone or low estradiol levels, or both; these patients made up Group I. Group II patients showed a rapid drop in the progesterone and estradiol values after stimulation therapy despite ongoing pregnancy. The third group comprised women with PCO syndrome, who had previously anovulation or corpus luteum insufficiency. The pregnancy rate was 66.7%. In 9.8% a biochemical pregnancy was diagnosed through the hormone measurements. These biochemical pregnancies were not influenced by Gravibinon treatment. In 3.9% an empty cavity was found. In 11.8% abortion occurred prior to the 16th week of gestations despite Gravibinon treatment. In 7.8% late abortions occurred. In one case pregnancy was terminated owing to chromosomal anomalies. The pregnancy rate in all three groups was nearly equal, with group I at 20%, group II at 21.4%, and group III at 20%. In these high-risk groups it was found that treatment with an estrogen/progestin combination such as Gravibinon appears to be an effective treatment of an endangered pregnancy. An increased risk of specific anomalies was not observed.

LH pulses and the corpus luteum: The luteal phase deficiency (LPD)

The proper function of the GnRH pulse generator in the hypothalamus is essential for normal ovarian function, hence also for proper function of the corpus luteum. During the luteal phase LH pulses stimulate progesterone release, which is essential for normal endometrial transformation. Approximately one-half of all luteal phase deficiencies (LPD) are due to improper function of the GnRH pulse generator. Obviously, following ovulation the increased serum progesterone levels oversuppress the GnRH pulse generator, resulting in too few LH pulses and therefore improper luteal function. Also, latent hyperprolactinemia may lead to an LPD which can be effectively treated with plant extracts containing dopaminergic (prolactin-suppressing) compounds. Our increasing knowledge of auto- and paracrine mechanisms between nonsteroidogenic and steroidogenic cells now allow subclassification of LPDs of ovarian origin. The so-called small luteal cells are LH-responsive. If they develop improperly the regularly occurring LH pulses are unable to stimulate progesterone secretion from the small luteal cells, which results in what we call the small luteal cell defect. In addition, there is also evidence that the large luteal cells may function improperly. Hence, basal progesterone release is too low while LH-stimulated progesterone release from the small luteal cells appears to be intact. This subclassification of luteal phase deficiency results in the suggestion of different treatments. In cases where the corpus luteum is LH-responsive, such as the hypothalamic corpus luteum insufficiency and the large luteal cell defect, HCG treatment or pulsatile treatment with GnRH is advisable. In the case of LH/hCG-unresponsive small luteal cell defect a progesterone substitution is suggested.

P08Case report: transvaginal ultrasonographic aspiration in the management of an ovarian cyst detected at the seventh gestational week

ObjectiveTo discuss a different approach, other than cystectomy, to an ovarian cyst detected at early gestation due to the risk of torsion.Case reportDuring ultrasonographic control of a pregnant at seven weeks of gestation, 30‐year‐old with two gravidity, one parity and one living child, a cyst with regular contour, measuring 150 × 130 mm with a wall thickness smaller than two mm was detected. By Doppler evaluation, vascular pattern could not be detected on the cyst wall. Ca 125, AFP, CEA levels were measured as 41.4 U/ml, 2.4 IU/ml, 1.2 ng/ml, respectively. The cyst was aspirated by a 17 g needle through posterior fornix with the assistance of tranvaginal ultrasonography. In cytological evaluation of the cyst fluid, no malignant cells were found. The case was called for control at 12th week of gestation which was known as the week of the completion of luteoplacental shift.ConclusionSince ca125 levels could be increased by pregnancy and there was no malignant feature except the dimensions of the cyst, the cyst was supposed to be benign and a conservative approach was planned. Corpus luteum is necessary for the continuation of pregnancy at these weeks of gestation so the anxiety about cystectomy was the termination of pregnancy due to corpus luteum deficiency. On the other hand, however, expectant management could not also be chosen, because the risk of torsion was high due to the texture, dimensions and mobile characteristic of the cyst. For this case who was at a younger age for ovarian malignancy the shrinkage of the cyst by aspirating it with the assistance of transvaginal ultrasonography without dysfunctioning corpus luteum, was decided. The management could be changed according to the cytological evaluation.In conclusion, at the early weeks of gestation, transvaginal cyst aspiration could be a way of management by decreasing the torsion risk without being a handicap for the continuation of pregnancy.

Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction.

The lats gene has been identified as a tumour suppressor in Drosophila melanogaster using mosaic screens. Mosaic flies carrying somatic cells that are mutant for lats develop large tumours in many organs. The human LATS1 homologue rescues embryonic lethality and inhibits tumour growth in lats mutant flies, demonstrating the functional conservation of this gene. Biochemical and genetic analyses have revealed that LATS1 functions as a negative regulator of CDC2 (ref. 3). These data suggest that mammalian LATS1 may have a role in tumorigenesis. To elucidate the function of mammalian LATS1, we have generated Lats1-/- mice. Lats1-/- animals exhibit a lack of mammary gland development, infertility and growth retardation. Accompanying these defects are hyperplastic changes in the pituitary and decreased serum hormone levels. The reproductive hormone defects of Lats1-/- mice are reminiscent of isolated LH-hypogonadotropic hypogonadism and corpus luteum insufficiency in humans. Furthermore, Lats1-/- mice develop soft-tissue sarcomas and ovarian stromal cell tumours and are highly sensitive to carcinogenic treatments. Our data demonstrate a role for Lats1 in mammalian tumorigenesis and specific endocrine dysfunction.

Influence of nicotine, cotinine, anabasine and cigarette smoke extract on human granulosa cell progesterone and estradiol synthesis

To reveal the well known effect of smoking on the incidence of early abortion, the possible effects of cigarette alkaloids on progesterone and estradiol synthesis were investigated. A suspected cause for early spontaneous abortion is corpus luteum insufficiency. The present experiments evaluate the effects of cigarette smoke alkaloids on progesterone and estradiol biosynthesis. Human granulosa cells were obtained from patients undergoing in vitro fertilization and embryo transfer treatment because of infertility. Incubation of the granulosa cells with cotinine, anabasine, with the combination of nicotine, cotinine and anabasine, or with an aqueous extract of cigarette smoke resulted in inhibition of progesterone synthesis. The alkaloids and smoke extract decreased the DNA content of the culture dish. These latter findings suggested a cytotoxic effect of the alkaloids. Both cotinine and anabasine slightly stimulated the synthesis of normalized estradiol. However, nicotine, combination of all three alkaloids, and cigarette smoke extract had no significant influence on estradiol production. Taken together, these data would suggest that cigarette alkaloids inhibit cellular progesterone synthesis both by inhibiting progesterone synthesis and by causing less specific toxic effects to the cell. In contrast, cigarette smoke alkaloids slightly stimulated or had no effect on estradiol production. These concomitant actions of cigarette alkaloids partly explain the higher incidence of early abortion in pregnant women who smoke.

Disturbed behavioural adaptability as related to reproductive hormones and emotional states during the menstrual cycle

The relationship between the incapacity to adapt behaviour to external requirements and biological irregularities of the menstrual cycle was investigated in 30 healthy females divided according to a questionnaire on behavioural adaptability into good (GAs) and bad (BAs) adaptors. Emotional states and blood samples for determination of hormones were obtained on ten defined days of the menstrual cycle, which were individually synchronized to six phases according to biological indicators. Comparison of GAs and BAs revealed that the incapacity of behavioural adaptation is associated with higher neuroticism related traits and states and that BAs exhibited higher cortisol and testosterone levels, lower luteal and follicular levels of estrogen, and lower luteal levels of progesterone. Furthermore, significantly more BA subjects suffered from corpus luteum deficiency. Results are discussed with respect to chronobiological biobehavioural mechanisms. © 1998 John Wiley & Sons, Ltd.

Regulation of Steroid Production and its Function Within the Corpus Luteum

During the second half of the luteal phase, the human corpus luteum becomes responsive to regular luteinizing hormone (LH) pulses. These LH pulses stimulate progesterone secretion tonically, and during this tonic stimulation, additional LH-independent progesterone pulses occur, which are particularly pronounced in women with human chorionic gonadotropin-stimulated luteal function. No progesterone pulses are seen in women suffering from corpus luteum deficiency due to absent LH pulses. The corpus luteum thus has a progesterone pulse generator turned on by gonadotropins but functioning for several hours without further gonadotropic support. This pulse generator appears to be regulated by intraluteal auto-/paracrine mechanisms, which we have investigated in a porcine model using molecular, cellular, and in vivo tools. Luteal oxytocin and progesterone release occurs in tightly coupled pulses. In vivo, oxytocin and prostaglandin F 2α(PGF 2α) stimulate estradiol and progesterone release and estradiol itself further stimulates progesterone release. Analysis of the different luteal cell compartments (large luteal cells, small luteal cells, fibroblasts) suggests an intraluteal circuit that involves paracrine effects of estradiol, oxytocin, and PGF 2α. At the time of luteolysis, the luteotropic effects of estradiol are inhibited by tumor necrosis factor derived from invading macrophages and the intraluteal circuit is thereby disrupted, leading to luteolysis.

Triggering Ovulation With GnRH Agonist, to Avoid Ovarian Hyperstimulation, Frequently Results in Profound Corpus Luteum Insufficiency

Triggering Ovulation With GnRH Agonist, to Avoid Ovarian Hyperstimulation, Frequently Results in Profound Corpus Luteum Insufficiency

P-170 Triggering ovulation with GnRH agonist, to avoid ovarian hyperstimulation, frequently results in profound corpus luteum insufficiency

P-170 Triggering ovulation with GnRH agonist, to avoid ovarian hyperstimulation, frequently results in profound corpus luteum insufficiency

The corpus luteum insufficiency: a multifactorial disease.

The pulsatile release pattern of LH during the entire menstrual cycle is well defined; however, the response of corpora lutea to these LH pulses in patients suffering from corpus luteum insufficiencies (CLI) is largely unknown. Patients suffering from CLI were selected from infertile patients on the basis of low progesterone (P < 25 nmol/L) in a blood sample withdrawn during a monitoring cycle. During the next cycle, nine blood samples were collected during the follicular and luteal phase and follicular development was assessed by vaginal sonography. Of 109 patients who had a CLI in the monitoring cycle, 55 had a CLI again, and 38 women agreed to undergo assessment of pulsatile hormone secretion. These women again had P < 25 nmol/L at days 6 and 7 of the luteal phase and blood samples were withdrawn through antecubital vein catheters from 0900-1700 h at 10-min intervals on days 7, 8, or 9 following ovulation. From 38 patients with such defined CLI, 16 (42%) had no LH episode and significantly lower basal LH levels in comparison with 14 control subjects. Thirteen (34%) of the patients had normal appearing LH episodes despite too low P and E2 concentrations, but their CL did not react to the LH episodes. The remaining 9 patients (24%) had normal LH episodes; their CL reacted to these episodes, but their basal P levels were too low. In all blood samples LH was not only determined using an immunoassay but also by the mouse Leydig cell testosterone production bioassay. It could be established that no CLI exists, which is due to the release of bioinactive LH. It is anticipated that the differentiation of three different types of CLI, one of hypothalamic and two of ovarian origin, may allow the development of differential diagnostic and therapeutic tools in the future.

The corpus luteum insufficiency: a multifactorial disease

The corpus luteum insufficiency: a multifactorial disease

Habitual abortion

Endocrine disorders are among the potential causes of repeated spontaneous abortion although their role is uncertain. These disorders most frequently associated with repeated spontaneous abortion are corpus luteum insufficiency, polycystic ovary syndrome, diabetes mellitus, and hypo- and hyperthyroidism. The best method of diagnosing corpus luteum insufficiency has not yet been established. It seems that treatment for this condition cannot be based on simple supplementation with progesterone, but ovulation induction preceded by pituitary suppression and human chorionic gonadotropin administration might be more successful. There is increasing evidence that polycystic ovary syndrome is a cause of repeated spontaneous abortion, but possibly only in the presence of oligomenorrhea and luteinizing hormone hypersecretion. Diabetes, if well controlled by treatment, and thyroid dysfunction, probably play a minor role.

Das Konzeptionsrisiko während der Stillperiode

The contraceptive effect of lactation is undisputed. Nursing increases the prolactin level in the serum. This hyperprolactinaemia suppresses all levels of the hypothalamus-hypophysis-ovary axis. The risk of ovulation can be greatly reduced by a proper nursing routine, frequency of nursing being credited with a greater anovulatory effect than duration of nursing. In addition, full nursing increases contraceptive safety. To prevent a drop in the serum prolactin level, nursing should also be done at night-time. Amenorrhoea during the lactation period is one of the most important prerequisites for an adequate contraception. The risk of ovulation increases dramatically, if vaginal bleeding occurs. However, the first cycles in the lactation period are often anovular and characterized by corpus luteum insufficiency. Lactation-induced amenorrhoea, nursing frequency of at least 6 x/day, nursing duration of at least 60 minutes/day, additional feedings of maximum 1 x/day and nocturnal nursing are the requirements for sufficient nursing-induced contraception. Even if these requirements are fulfilled, the risk of ovulation increases with the length of time post partum. Effective contraceptive protection is attained only up to the 9th p.p. week. If high post partum contraceptive safety is required, a mini-pill or micro-pill must be recommended. Lactation can only be recommended as a moderate contraceptive measure even in this case, an additional method (chemico-mechanical) should be initiated 3 months post partum.

Rationelle hormonale Diagnostik der normozyklischen funktionellen Sterilität*

Functional infertility in women with a normal menstrual cycle is the first symptom of a pathophysiological sequence of multiple different endocrinopathies. It usually progresses and leads to secondary amenorrhoea which is the most severe symptom of ovarian insufficiency. The percentage of abnormal hormonal parameters will increase with the duration and extent of the endocrinological aberration. The aim of this study is to examine the frequency of the different potential changes in hormone levels of an unselected group of female patients in a fertility clinic. 307 patients suffering from functional sterility (menstrual cycle 25-34 days) were investigated via basal hormone laboratory tests (including TRH test) under standardised conditions. 73 patients had pathological changes of the Fallopian tubes and in 116 patients their husbands had severe andrological problems. Excluded from this study were patients with bilateral occlusion of the Fallopian tubes and patients whose partners had a sperm count of less than 1 million/ml. The percentage of abnormal hormone levels (greater than mean + standard deviation + grey area) was 32.2% for prolactin (PRL), 7.8% for TSH, 20.9% for Delta-TSH, 18.4% for DHEA-sulfate (DS), 9.8% for testosterone (T), 18.9% for LH, and 11.5% for FSH (LH and FSH were specifically calculated only in 87 patients). In 65.5% of the patients the midluteal oestradiol (E2) and progesterone (P) levels were below normal, as sign of a corpus luteum insufficiency (CLI). A step- by-step diagnostic procedure would have yielded the following cumulative abnormal hormone levels retrospectively: (1) PRL (n = 99) = 32.2% (2) +TSH/delta TSH (n = 85) = 48.9% (3) +DS (n = 56) = 58.0% (4) +T (n = 30) = 59.3% (5) +LH/FSH (n = 28) = 62.2% [(6) +E2/P (n = 201) = 82.7%.] Only in 37.8% (116 patients) all hormone levels were within normal limits during the early follicular phase (FP); if the patients with signs of CLI are added, the percentage would be only 17.8% (n = 53). Case analysis demonstrated that functional sterility was accompanied by hyperprolactaemia in 32.4% of all patients, by abnormalities of the thyroid function (hypothyroidism 16.0%, hyperthyroidism 7.8%) in 23.8%, by hypothalamic and/or pituitary dysfunction in 28.7%, and by hyperandrogenaemia in 22.5%. Primary ovarian insufficiency was diagnosed in 4.6%. 31.3% of all patients (n = 307) had a combination of different hormonal abnormalities. The average duration of infertility among this group of patients was 6.3 years.(ABSTRACT TRUNCATED AT 400 WORDS)

Screening infertile women for the assessment of corpus luteal function and their response to therapy by ELISA of pregnanediol glucuronide

Corpus luteal function was assessed by estimating pregnanediol 3-α-glucuronide (PdG) in three midluteal-phase urine samples collected from 85 women attending the infertility clinic. The previously established cut off limits based on PdG estimations were useful in detecting anovulation in 23 cases, corups luteal adequacy in 42 cases and corpus luteum deficiency (CLD) in 20 cases. In 8 women CLD could be corrected with 50 mg of clomiphene citrate (CC) therapy whereas 6 women required 100 mg of CC and 3 pregnancies were achieved. This rapid screening method is thus useful in segregating a large number of women according to their ovulatory status and in the subsequent treatment of CLD.

Levels of serum steroid hormones in intrauterine contraceptive device users

Serum progesterone, estradiol, testosterone and cortisol were assayed in the mid-follicular and mid-luteal phases of the menstrual cycles in 30 Lippe's loop and 30 Cu T-200 IUCD users, compared to 24 controls. Mean serum progesterone and estradiol levels were significantly higher in the mid-luteal, compared to the mid-follicular phase in each group (p less than 0.01). There were no significant differences between the mean levels of progesterone, testosterone and cortisol in IUCD users and controls in both the mid-follicular and mid-luteal phases. IUCD users had significantly higher levels of estradiol (p less than 0.01) in the mid-luteal phase but not in the mid-follicular phase, compared to controls. There was hormonal evidence of corpus luteum insufficiency in 8.3%, 14.3% and 20% in the controls, Lippe's loop and Cu T-200 IUCD users, respectively.

Ovulation Induction for Corpus Luteum Deficiency

Ovulation Induction for Corpus Luteum Deficiency

The endometrium in natural and artificial luteal phases.

The normal human endometrium reacts precisely and sensitively to any hormonal stimulation with predictable changes. If the corpus luteum develops normally after ovulation, the progesterone secreted induces specific changes in endometrial glandular and stromal cells that can be dated by daily fine-structural alterations. With corpus luteum deficiency the endometrial differentiation is delayed and remains incomplete. The defect in the differentiation of glands and stroma varies in their distribution and intensity and may be dissociated or coordinated depending upon the cause of the corpus luteum deficiency. The administration of natural progesterone in the second half of the cycle prolongs the luteal phase and may result in hypersecretion of glands. In contrast, therapy with synthetic gestagens depresses glandular secretion, induces glandular atrophy and decidualization of the stroma. The various synthetic gestagens differ both quantitatively and qualitatively in their action; depending upon the dosage given the endometrium remains in abortive or arrested secretion. Clomiphene depresses normal secretion by its antioestrogenic effect which causes deficient oestrogen priming. On the other hand, clomiphene counteracts excessive oestrogen and will normalize the secretion in a deficient luteal phase that was preceded by follicular persistency. In the artificial cycle, depending upon the state of endogenous hormonal stimulation, the patients will benefit either from clomiphene or gonadotrophin to maintain or normalize their secretory endometrium.

Corpus luteum insufficiency and fertility: a matter of controversy.

This paper analyses different controversial aspects of luteal phase deficiency (LPD) on the basis of our own data and current clinical experience. Conceptual and diagnostic concerns include: (i) the lack of predictive value of mid-luteal plasma progesterone determinations regarding the progestational transformation of the endometrium, and (ii) the need for a minimum of two, or even three, endometrial biopsies for diagnosis of LPD. From an aetiologic point of view follicular phase determinants of LPD are emphasized and conflicting data on claimed predisposing factors of LPD are analysed. Primary therapeutic approaches to LPD and the effectiveness and significance of such therapy on fertility are discussed.

Corpus luteum insufficiency induced by a rapid gonadotropin-releasing hormone-induced gonadotropin secretion pattern in the follicular phase.

The pulse frequency of LH and FSH (and by inference, GnRH) is a major determinant of the relative baseline plasma levels of LH and FSH. Luteal phase deficiency has been reported to be associated with increased gonadotropin pulse frequency and inadequate preovulatory follicular development. In this study we induced in normal women a supraphysiological gonadotropin pulse frequency in the follicular phase to determine its effect on follicular development and corpus luteum function. Specifically, we tested the hypothesis that a supraphysiological GnRH pulse frequency would result in deficient luteal phase production of progesterone. The subjects were six normal ovulatory women (age range, 23-35 yr). They were initially studied during a control cycle (cycle 1). Then, 25 ng/kg GnRH was administered iv every 30 min from the early follicular phase of the next cycle (cycle 2) until ovulation occurred. GnRH administration resulted in increased follicular phase plasma LH and FSH levels and LH to FSH ratios, multiple preovulatory follicles (mean, 2.8) with increased mean integrated estradiol [1302 (pg/mL)day (cycle 1) vs. 2550 (pg/mL)day (cycle 2); P less than 0.05; 4780 vs. 9360 (pmol/L)day, Systeme International units], spontaneous ovulation, decreased luteal phase plasma immunoreactive and bioactive LH levels, decreased luteal phase length [13.5 days (cycle 1) vs. 8.8 days (cycle 2); P less than 0.05], and decreased mean integrated progesterone secretion [152 (ng/mL)day (cycle 1) vs. 66 (ng/mL)day (cycle 2); P less than 0.01; 482 vs. 209 (nmol/L)day, Systeme International units]. We conclude that high frequency LH and FSH secretion during the follicular phase can induce inadequate progesterone secretion during the subsequent luteal phase, and we infer that the pathophysiological basis for this induced luteal phase deficiency is decreased LH support of corpus luteum function.