Luteal Deficiency Research Articles

ALTRENOGEST AND PROGESTERONE THERAPY DURING PREGNANCY IN BOTTLENOSE DOLPHINS (TURSIOPS TRUNCATUS) WITH PROGESTERONE INSUFFICIENCY

Progesterone production is essential for growth and development of the conceptus during pregnancy. Abnormal development of the corpus luteum (CL) after conception can result in early embryonic loss or fetal abortion. Routine monitoring of bottlenose dolphin (Tursiops truncatus) pregnancy after artificial insemination or natural conception with ultrasonography and serum progesterone determination has allowed for the establishment of expected fetal growth rates and hormone concentrations. Using these monitoring techniques, we revealed four pregnant dolphins (12-24 yr old) with abnormally low progesterone production indicative of luteal insufficiency. Once diagnosed, animals were placed on altrenogest (0.044-0.088 mg/kg once daily) alone or with oral progesterone (50-200 mg twice daily). Doses of hormone were increased or decreased in each animal based on how fetal skull biparietal and thoracic growth rates compared with published normal values. Hormones were withdrawn starting from day 358 of gestation in animals 1 and 2, with labor occurring 6 and 7 days after withdrawal and at 376 and 373 days of gestation, respectively. Both deliveries were dystocic, with each calf requiring manual extraction and fetotomy for calf 1. The fetuses in animals 3 and 4 died at 348 and 390 days of gestation, respectively. Induction of labor was attempted in both animals, after fetal death, by using a combination of rapid progesterone withdrawal and steroid and prostaglandin F2alpha administration. The calf of animal 4 had to be removed with manual cervical dilation and fetotomy All adult females survived the procedures. These data provide the first in vivo evidence that the CL is the primary source of progesterone throughout pregnancy in the bottlenose dolphin. Until further characterization of hormones required during pregnancy and at parturition has been accomplished, the exogenous progestagen supplementation protocol described here cannot be recommended for treatment of progesterone insufficiency in bottlenose dolphins.

Gestación en paciente con tratamiento renal sustitutivo

La frecuencia de embarazo en mujeres sometidas a hemodiálisis es baja (entre 0,3 y 0,75% año mujeres en edad fértil)1. Este hecho se atribuye a diferentes factores hormonales, muchos de ellos anovulatorios: hiperprolactinemia, disfunción ovárica con anovulaciones, insuficiencia lútea, disminución de la libido (debido a alteraciones de los pulsos de la gonadotropina coriónica humana), niveles aumentados de leptina (por disminución de su aclaramiento renal), anormalidades del eje pituitario ovárico2. Cuando se produce un caso de embarazo en una paciente de HD, independientemente del criterio que se siga, la prescripción de la hemodiálisis debe ser suficiente para mantener estables las condiciones maternas en relación al volumen circulante, presión sanguínea (= 140/80 a 90 mm Hg 7,8,10) y la ganancia ponderal interdialítica. La prescripción de la ultrafiltración se debe individualizar para evitar episodios de hipovolemia, hipotensión arterial y arritmia cardiaca materna. Se debe ajustar para respetar la ganancia ponderal y la expansión del volumen sanguíneo materno que corresponde al tiempo de la gestación1. Los trastornos metabólicos son una de las partes más difíciles de manejar. Las concentraciones ideales de hemoglobina y de hematocrito oscilan entre 11-12 mg/dl y entre 33-36% respectivamente. Se debe mantener un control de la misma manera de calcio, fosforo y potasio.

Premature luteal regression in a pregnant mare and subsequent pregnancy maintenance with the use of oral altrenogest

Premature luteal demise or luteal insufficiency is not well characterised as a cause of pregnancy loss in domestic species, including horses. In this report, a mare inseminated with cooled-transported semen at our facility returned for a routine pregnancy diagnosis at 15 days post ovulation. Ultrasonography per rectum revealed endometrial oedema and the absence of visual indication of a corpus luteum on either ovary. Nonetheless, an embryonic vesicle small for the gestational age was identified. Daily oral altrenogest treatment was implemented immediately. Serum progesterone concentration was 0.67 ng/ml, which is below the threshold considered adequate for pregnancy maintenance in the mare. Examinations were repeated at 17, 25, 30, 39, 49, 72 and 120 days post ovulation. At 25 days post ovulation the embryonic vesicle presented normal development for the gestational age. In addition, sequential blood samples were collected to measure progesterone, equine chorionic gonadotrophin and oestrone sulphate concentrations. Although progesterone concentration did not exceed 2 ng/ml until 72 days post ovulation, all other results were unremarkable and a healthy filly was born uneventfully at 344 days post ovulation.

The effect of micronutrient supplements on female fertility: a systematic review

Assessment of the influence of vitamins, trace elements and multivitamin supplements on female fertility. Systematic review of published controlled trials and cohort studies investigating the effect of vitamin supplements on female fertility. 13 studies with a total of 90,004 female test persons and patients. oral, preconceptional administration of single or combination of vitamin supplements; experimental studies, pharmacological studies, case control studies, case reports, reviews, meta-analysis. Women with chronic diseases, genetic or physical causes for (primary) sterility, couples with an impaired fertility of both partners; patients undergoing reproductive medicine care (insemination, in vitro fertilization, IVF, intracytoplasmatic sperm injection, ICSI). Determination of the proportion of women that experienced an influence of vitamin supplements on their fertility. Thirteen relevant trials out of 37 studies were included. Some studies suggest a possible effect of micronutrients on female fertility. Emphasized results, for example, were an association between multivitamin substitution on pregnancy rate as well as higher vitamin B6 levels in fertile women compared to infertile women. One randomised controlled study showed a positive effect of vitamin C in women with luteal insufficiency. Although some studies suggest possible effects of micronutrients on female fertility general recommendations are not possible since all studies had methodological or statistical limitations. Further investigations using evidence-based criteria are necessary to analyze and to confirm these non-evident appearances.

T helper (Th)1, Th2, and Th17 interleukin pathways in infertile patients with minimal/mild endometriosis

In the present study, interleukin (IL)-10, IL-12, IL-17, and IL-23 levels were measured in serum and peritoneal fluid of women with minimal or mild endometriosis and compared with levels in controls without endometriosis. Higher IL-23 levels were encountered in the peritoneal fluid of women with endometriosis, suggesting a possible role of this cytokine in these women's infertility.

Subfertility Linked to Combined Luteal Insufficiency and Uterine Progesterone Resistance

Early pregnancy loss is common and can be caused by a range of factors. The Brown Norway (BN) rat exhibits reproductive dysfunction characterized by small litter size and pregnancy failure and represents a model for investigating early pregnancy loss. In this study, we investigated the establishment of pregnancy in the BN rat and gained insight into mechanisms causing its subfertility. Early stages of BN uteroplacental organization are unique. The BN primordial placenta is restricted in its development and correlates with limited BN uterine decidual development. BN uterine decidua was shown to be both structurally and functionally distinct and correlated with decreased circulating progesterone (P4) levels. Ovarian anomalies were also apparent in BN rats and included decreased ovulation rates and decreased transcript levels for some steroidogenic enzymes. Attempts to rescue the BN uterine decidual phenotype with steroid hormone therapy were ineffective. BN uteri were shown to exhibit reduced responsiveness to P4 but not to 17beta-estradiol. P4 resistance was associated with decreased transcript levels for the P4 receptor (Pgr), a P4 receptor chaperone (Fkbp4), and P4 receptor coactivators (Ncoa1 and Ncoa2). In summary, the BN rat exhibits luteal insufficiency and uterine P4 resistance, which profoundly affects its ability to reproduce.

Endocrine alterations around the time of abortion in mares impregnated with donkey or horse semen

The objective of this study was to monitor and compare the concentrations of equine chorionic gonadotropin (eCG), progesterone and estrone sulphate during normal and failed pregnancies of mares impregnated with donkey or horse semen, relating their individual endocrine profiles to the time of pregnancy loss, and to the histopathologic findings in the aborted fetuses and placenta. Mares ( n = 54) were used, 32 of them impregnated with donkey semen and 22 impregnated with horse semen. Blood samples were taken twice a week from Day 35 to 120 of pregnancy. Ultrasonographic observations of the fetus were carried out twice a week. The incidence of abortion in mares impregnated with donkey semen (30%) was greater ( P < 0.05) than the 5% observed in mares impregnated with horse semen. From Week 8 to the end of the sampling period, the mean progesterone concentrations of mares with normal mule pregnancies were less ( P < 0.05) than those of mares with normal pregnancies with equine fetuses. The concentrations of eCG were less ( P < 0.05) in mule pregnancies from Week 6. Estrone sulphate concentrations were only different ( P < 0.05) between types of pregnancy on Weeks 13 and 14, being in this case greater with the mule pregnancies. Most of the abortions of mule fetuses were associated with lesser progesterone concentrations than the average for mares with successful mule pregnancies. Four of the abortions of mule fetuses and the only abortion of horse fetus occurred in mares with lesser progesterone and very low eCG concentrations, and were classified as caused by luteal impairment secondary to eCG deficiency; estrone sulphate concentrations were less than normal or absent before these abortions. Two mares aborted after several weeks of low progesterone concentrations in the presence of eCG concentrations that were normal for mule pregnancies, suggesting primary luteal deficiency. In three mares carrying a mule fetus, the concentrations of progesterone and estrone sulphate decreased abruptly immediately before fetal death, suggesting luteolysis due to active prostaglandin F2 alpha (PGF2α) secretion. It is concluded that the greater incidence of abortion in mares impregnated by donkeys is associated with different kinds of luteal malfunction. Deficiency of eCG may be a primary cause of many of these cases, either by failing to stimulate enough luteal progesterone secretion and/or by failing to protect the corpora lutea (CL) of pregnancy from endogenous PGF2α secretion.

Endocrinological studies and clomiphene therapy of luteal insufficiency.

We investigated the hormonal situation of 91 patients with luteal insufficiency in order to clarify its etiology. Their gonadotropin and estradiol (E2) values in the late follicular phase and progesterone value in the luteal phase were lower than normal menstrual cycle women. Especially, in about 50% of these patients, their gonadotropin value in the late follicular phase was lower than that of normal menstrual cycle women. Eight cases had higher LH values than normal women. Clomiphene was administrated to develop follicular maturation. The effectiveness of clomiphene therapy was 62% and the pregnancy rate was 25%. Hormonal investigation and therapeutical effects support the observation that many cases of luteal insufficiency are due to immature follicular growth in the late follicular phase.

Progesterone, Oestradiol, FSH and LH Concentrations in Serum of Progesterone‐Treated Pregnant Bitches with Suspected Luteal Insufficiency

In the bitch, the corpus luteum is the only source of circulating progesterone throughout pregnancy. Inadequate luteal function may be a cause of abortion or foetal resorption observed after early pregnancy diagnosis. In our study of factors involved in canine luteal inadequacy, 35 pregnant bitches from different breeds were allocated to groups of healthy control (n = 15) vs hypoluteoid (n = 20) pregnant bitches, based on presence or absence of clinical signs of impending abortion and on progesterone concentrations below 10 ng/ml at the 4th-5th week of pregnancy. Hypoluteoid bitches were treated daily with 10-mg natural progesterone in injectable form (Luteosan inj.; Alvetra and Werfft AG, Vienna, Austria) until day 60. Serum progesterone, 17beta-oestradiol, FSH and LH concentrations were measured in samples obtained weekly using ELISA previously validated for dog serum. The exogenous progesterone supplementation was presumed to be sufficient to prevent foetal loss in 15 of the 20 treated bitches. The mean serum progesterone concentration in control pregnant bitches did not decrease below 10 ng/ml until the 8th week of pregnancy. Progesterone concentrations in progesterone-treated hypoluteoid bitches at week 4 were lower than in controls (p < 0.05), but although numerically higher did not differ significantly from those of controls during the period of treatment. Serum 17beta-oestradiol concentrations of healthy bitches were variable, were at most time higher than those of treated animals and slowly decreased until parturition; those of treated bitches remained unchanged during the study. Serum FSH and LH concentrations did not differ between groups. Additional studies involving untreated pregnancies showing equivalent evidence of hypoluteoidism as well as assay of circulating relaxin and prolactin in treated and untreated bitches are needed to better determine the causes and effects of hypoluteoidism in pregnant bitches.

Influence of Progesterone Withdrawal on Pregnancy‐Related Parameters During Post‐Implantation Early Pregnancy Loss

Pharmacologically-induced luteolysis or treatment with an antiprogestin in early post-implantation pregnancy in dogs results in asynchronous death and resorption of conceptuses, indicating variable rates of response of individual conceptuses towards progesterone deficiency. This variability also seems to occur in bitches showing pregnancy failure in response to spontaneous luteal deficiency. In a total of 10 beagle pregnancies (two consecutive pregnancies of five bitches), abortifacient treatments beginning on day 24 after ovulation (ov) involved either administration of a progestin antagonist (total of six pregnancies, in three bitches) or a luteolytic regimen of prostaglandin F(2alpha)-analogue together with a dopamine agonist (total of four pregnancies, in two bitches). The outcomes were evaluated in relation to four control pregnancies in two bitches by assay of serum progesterone, prolactin and relaxin at selected time points or within selected time periods, by ultrasound of conceptuses including measurement of uterine blood flow, and parameters of the blood fibrinolytic system including plasma fibrinogen and plasminogen. The process of embryonic death and conceptus resorption was variable in onset and duration both in bitches that received the progesterone antagonist aglepristone (AGLE) and in those under the luteolytic treatment (cloprostenol combined with cabergoline). Pregnancy termination (death of all embryos or foetuses, respectively) occurred as early as day 29 and as late as day 41 after ov in AGLE-treated bitches, and not earlier than day 37 after ov in luteolytic-treatment bitches. Impending embryonic death was not predicted by changes in relaxin concentration, parameters of the fibrinolytic system, or in the perfusion of small uteroplacental vessels.

146. MACROPHAGES ARE ESSENTIAL FOR MAINTENANCE OF EARLY PREGNANCY THROUGH REGULATION OF CORPUS LUTEUM FUNCTION

Macrophages are abundant within the ovary, and have been identified in the corpus luteum (CL) of most species studied, including in rodents and human. Through their secretory products, macrophages are thought to be involved in ovarian tissue remodelling, including luteinization, and in regulating steroidogenesis [1, 2]. Macrophages co-cultured with granulosa or luteal cells act to stimulate progesterone secretion [3]. To determine the impact of macrophage ablation during early pregnancy, we utilised the macrophage specific CD11b-DTR diphtheria toxin receptor (DTR) transgenic mouse to cause transient systemic ablation of macrophages via the administration of DT (25 ng/g). The effects of macrophage ablation during the pre-implantation phase of pregnancy were evaluated and implantation sites were counted. Ablation of macrophages on day 1 pc (n=13 wild-type; n=9 CD11b-DTR) or day 4 pc (n=6 CD11b-DTR; n=9 wild-type) caused complete pregnancy loss in all DT-treated CD11b-DTR mice, while wild-type mice maintained viable pregnancies [mean ± SEM implantation sites = 5.0 ± 1.4 (day 1 treated), and 6.0 ± 1.9 (day 4 treated)]. Serum progesterone was analysed 24 h following macrophage ablation. A single DT injection on day 3 pc significantly reduced serum progesterone (P4) levels [n=7 wild-type P4 (ng/ml)= 29.6 ± 3.3; n=8 CD11b-DTR = 11.1 ± 2.1]. The administration of exogenous P4 (2 mg) on each of day 4-7 pc prevented fetal loss in DT-treated CD11b-DTR mice (n=6; implantation sites = 7.8 ± 1.6), while no pregnancies remained viable in DT-treated mice administered vehicle only (n=9). In conclusion, luteal insufficiency appears to be the cause of pregnancy failure following macrophage ablation. These data indicate a critical role for macrophages in corpus luteum function in early pregnancy.

Sustained-Release Progesterone Vaginal Suppositories 1-Development of Sustained-Release Granule-

Progesterone (P) is an important hormone for the establishment of pregnancy, and its administration is useful for luteal insufficiency. Considering the problems of commercially available oral and injection drugs, hospital-formulated vaginal suppositories are clinically used. However, since the half-life of P suppositories is short, it is difficult to maintain its constant blood concentration. To sustain drug efficacy and prevent side-effects, we are attempting to develop sustained-release suppositories by examining the degree of sustained-release of active ingredients. In this study, we examined the combinations of granulation methods and release systems for the preparation of sustained-release granules of P, and produced 13 types of sustained-release granules. We also examined the diameter, content, and dissolution of each type of granules, and confirmed that the sustained-release of all types of granules was satisfactory. Among the sustained-release granules, we selected granules with a content and a degree of sustained-release suitable for sustained-release suppositories.

Problems After Breeding

Breeding induces an inflammatory response in the uterus. The inflammation is a physiological reaction with the purpose of clearing the uterus from excess spermatozoa, seminal plasma, and bacterial contamination. Breeding-induced endometritis is transient and most mares resolve the inflammation within 24 to 36 hours. If a mare fails to resolve the breeding-induced inflammation before an embryo enters the uterus, the pregnancy is likely to be lost. Susceptibility to persistent breeding-induced endometritis occurs in approximately 15% of a normal brood mare population. Persistent breeding-induced endometritis can be diagnosed by ultrasonographic monitoring of the uterus for fluid accumulation at 6 to 24 hours after breeding. Mares that accumulate fluid beyond 6 to 12 hours after breeding, or have a history of persistent breeding-induced endometritis, should be treated with ecbolics and/or uterine lavage to help remove the inflammatory fluid from the uterus. Recent reports suggest that some mares with a history of severe breeding-induced endometritis may benefit from corticosteroid treatment around the time of breeding. Supplementation with exogenous progestin during early gestation may also be beneficial in mares with endometritis or other causes of secondary luteal deficiency.

Recent developments in the diagnosis and therapy of repeat breeding cows and buffaloes.

Abstract Repeat breeding (RB) continues to be a big problem for breeders and veterinary clinicians. A brief mention is made of the common aetiological and risk factors for RB in cattle and buffaloes, and the possible diagnostic and therapeutic approaches are described in detail. Important diagnostic tools could include rectogenital palpation, vaginoscopy, uterine cytology and the in vivo imaging technique of ultrasonography. When considering the most common causes of RB, vaginoscopy and palpation continue to be the only diagnostic tools available to clinicians at many locations, while by using ultrasonography, diagnostic accuracy can be increased markedly, especially when dealing with individual cows or buffaloes. Contrarily, when dealing with herds, metabolic profiles and sampling to detect infectious disease must be the clinicians' choice. Of pertinent consideration are the management regimens and feeding practices. Despite the development of many diagnostic procedures such as hormone assays, colour Doppler sonography, and hysteroscopy, diagnosing the cause of pregnancy failure in an individual cow/buffalo continues to be difficult, as a proportion of animals demonstrate obscure infertility. The choice of a therapeutic regimen depends on the possible cause of RB. Recent advances in the therapy of endometritis include the use of immunomodulators such as Escherichia coli lipopolysaccharide, use of eicosanoid PGF 2 α and therapy with enzymes with or without therapy with antibiotics, the use of which continues to be debatable. The therapy of ovulation induction in various ovulatory disturbances includes regimens utilizing hCG, GnRH, prostaglandins and their combinations. It appears that RB animals with aberrations of oestrus cycle do demonstrate such ovulation asynchronies. Suprabasal progesterone concentration at oestrus is thought to be an important contributor of RB, but remediation of this is largely unknown although reducing stress appears to be a probable method. Luteal insufficiency can be resolved by administration of hCG and GnRH or progestagens. A brief mention is made of ways of improving management and insemination procedures.

Evaluation of GnRH treatment 12 days after AI in the reproductive performance of dairy cows

The objective of this study was to evaluate the effects of GnRH administered at Day 12 post-AI on the reproductive performance of dairy cows. Holstein–Friesian dairy cows ( n = 103) on a large Hungarian dairy farm were allocated randomly to treated ( n = 54) or control ( n = 49) groups. Twelve days after AI, treated cows received a GnRH agonist i.m., while the control group received a placebo (physiological saline). Progesterone radioimmunoassay was used to determine the correct timing of artificial insemination (Day 0) and the incidence of luteal insufficiency on Day 12. Ultrasonography and radioimmunoassay for pregnancy-associated glycoprotein were used to detect pregnancy and late embryonic/fetal mortality between Days 32 and 55 after AI. Three cows from each group were inseminated when progesterone concentrations were >1.0 ng/mL, and six cows (four from the treated and two from the control group) had luteal insufficiency (progesterone < 1.0 ng/mL) on Day 12. Late embryonic/fetal mortality occurred in three treated cows and in two control cows. When these cows were removed from the model, calving rates after first service were 59.6% (28/47) and 59.1% (26/44) for treated and control cows, respectively ( P > 0.05). There was no significant difference between treated and control cows when they were inseminated before or after Day 100 from calving. In summary, administration of a GnRH agonist on Day 12 after AI did not improve reproductive performance in dairy cows. However, our approach may be used for the field evaluation of different treatment protocols.

Contraception in women over 35

Choice of a contraceptive method for a woman over 40 should take into account age related factors including declining fecundity increasing risks of vascular disorders and uterine pathology and the impending menopause. Female fecundity declines after age 25 and more rapidly after 40 because of chromosomal ovulatory and uterine alterations and the increasing frequency of genital tract inflammation. Declining frequency of sexual relations and declining fecundity of the partner are also involved. Because of the fecundity decline contraceptive methods considered less effective for younger women such as vaginal spermicides the condom and the diaphragm may be very effective for older women. Vascular risks increase with age and combined oral contraceptives (Ocs) aggravate the risks. The upper limit for OC use is still considered to be 35 years for women who smoke but women over 40 in good health who do not smoke may use OCs containing less than 50 mcg of ethinyl estradiol to decrease the thromboembolic risk. OCs containing desogestrel gestodene or norgestimate should be chosen because they are less androgenic and more favorable for lipid metabolism. Progestin-dominant combined OCs and injectable progestins have a protective effect against endometrial hyperplasia polyps fibromas and other benign uterine pathology induced by the relative hyperestrogenic state of perimenopausal women and against endometrial cancer. Women over 40 should continue to use contraception until the menopause. Women over 45 not under hormonal treatment who have been amenorrheic for over a year may safely discontinue contraception. Women using combined OCs should switch to a nonhormonal method at age 50 which can be discontinued after 12 months of amenorrhea. Alternatively the FSH level can be assessed three months after discontinuation of the pill to determine whether levels are menopausic. During the perimenopause a pill containing 20 mcg of ethinyl estradiol may be used but contraindications to combined OCs must be rigorously respected. Low-dose oral progestins may be used in case of contraindications to combined OCs but entail the disadvantages of irregular cycles and aggravation of luteal insufficiency. The IUD is a suitable method for older women with stable sex lives. Barrier methods offer protection against sexually transmitted diseases are relatively inexpensive and have a higher efficacy rate than among younger women.

中小病院における院内製剤の品質評価―プロゲステロンちつ坐剤―

Progesterone (P) is an important hormone for achieving pregnancy, and administering it is a useful therapy for luteal insufficiency. However, owing to problems with existing oral preparations and injections, P is increasingly administered by the transvaginal route in suppository form in medical institutions. Since vaginal suppositories are not commercially available, each institution has to prepare its own.For P-containing vaginal suppositories prepared in our hospital, we conducted hardness, weight variation, content uniformity, and elution tests as well as a 6-month stability test in cold storage and pharamacodynamics testing in vivo. The results confirmed that they were uniform in quality and stable, and valid for use as pharmaceutical preparations in clinical practice.Furthermore, the sustained-release suppositories prepared by us were found to maintain adequate blood levels of P.

Effects of Nicotine on Human Luteal Cells In Vitro: A Possible Role on Reproductive Outcome for Smoking Women1

We investigated the effect of nicotine and its methylated metabolite, N-methyl-nicotine (M-nicotine), on human luteal cells by measuring release of progesterone and prostaglandins (PGs) from cultured cells and by testing gene expression of vascular endothelial growth factor (VEGF), an angiogenic factor strictly involved in luteal pathophysiology. Primary cultures of human luteal cells were treated for 24 h with nicotine and M-nicotine (from 10(-6) to 10(-11) M) either alone or combined with hCG (25 ng/ml); progesterone and PGs were assayed in the culture medium. In another group of experiments, luteal cells were treated for 24 h with nicotine and M-nicotine (10(-7) M) to perform reverse transcriptase-polymerase chain reaction on VEGF mRNA. Nicotine and M-nicotine negatively affected basal luteal steroidogenesis at all tested concentrations, but neither was able to affect hCG-induced progesterone release. Both substances were able to significantly increase PGF2alpha release from luteal cells, with a dose-related efficacy for M-nicotine. On the contrary, PGE2 release was significantly inhibited by both nicotine and its metabolite. Finally, nicotine was able to increase VEGF mRNA expression significantly, whereas M-nicotine was not. In conclusion, nicotine and M-nicotine can induce a sort of luteal insufficiency by inhibiting progesterone release, probably through modulation of the PG system.

Endogenous sex hormones and subsequent breast cancer in premenopausal women.

Because of large intra-individual variation in hormone levels, few studies have investigated the relation of serum sex hormones to breast cancer (BC) in premenopausal women. We prospectively studied this relation, adjusting for timing of blood sampling within menstrual cycle. Premenopausal women (5,963), recruited to the Hormones and Diet in the Etiology of Breast Tumors (ORDET) cohort study, provided a blood sample in the 20-24th day of their menstrual cycle. After 5.2 years of follow-up, 65 histologically confirmed BC cases were identified and matched individually to 4 randomly selected controls. Sera, stored at -80 degrees C, were assayed blindly for dehydroepiandrosterone sulfate, total and free testosterone (FT), androstenedione, androstanediol-glucoronide, progesterone, 17-OH-progesterone, sex hormone-binding globulin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Fifty-five cases had information for multivariate analyses. Compared to controls, BC cases had shorter cycles and intervals between blood sampling and bleeding, and lower LH and FSH. FT was significantly associated with BC risk: relative risk (RR; adjusted for age, body mass index and ovarian cycle variables) of highest vs. lowest tertile was 2.85 [95% confidence interval (CI) = 1.11-7.33, p for trend = 0.030]. Progesterone was inversely associated with adjusted RR for highest vs. lowest tertile of 0.40 (95% CI = 0.15-1.08, p for trend = 0.077), significantly so in women with regular menses, where adjusted RR was 0.12 (95% CI = 0.03-0.52, p for trend = 0.005). These findings support the hypothesis that ovarian hyperandrogenism associated with luteal insufficiency increases the risk of BC in premenopausal women.

Pharmacokinetics of Natural Progesterone Vaginal Suppository

Natural and synthetic progesterone have been used to treat luteal insufficiency, premenstrual syndrome, and in infertile patients. The transvaginal route has advantages, such as lack of local pain, avoidance of first-pass hepatic metabolism, rapid absorption, high bioavailability and local endometrial effect. The aim of this study was to evaluate the pharmacokinetic of natural progesterone administered as vaginal suppositories of 25, 50 or 100 mg. Thirty-five healthy ovulating patients, 31.54 ± 1.29 (mean ± SEM) years old, in the follicular phase of the menstrual cycle (between days 7 and 10) participated in the study. They were separated in three groups and received vaginal suppositories containing either 25, 50 or 100 mg of natural progesterone. Progesterone serum concentration reached maximal levels within 2 or 3 h after the administration and was similar for the three groups (7.27 ± 2.8 ng/ml; 8.84 ± 3.14 ng/ml; 9.82 ± 9.8 ng/ml, respectively). This study demonstrated that vaginally administered progesterone could reach levels that are similar to those obtained in ovulatory and luteal phases. The progesterone regimen for adequate endometrial protection and in vitro fertilization (IVF) programs still remains to be studied.