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Progesterone is essential for endometrial receptivity and successful establishment of pregnancy. Either an insufficient progesterone concentration or an insufficient response to progesterone, therefore can lead to infertility and pregnancy loss. Assessment of the role that either progesterone insufficiency or inadequate progesterone response plays in human reproductive failure has been difficult to assess because serum progesterone concentrations fluctuate markedly, limiting the ability to characterize sufficiency of progesterone, and there are no highly reliable markers of endometrial function available. Recent evidence demonstrates exquisite sensitivity of normal endometrium to very low levels of progesterone stimulation, suggesting that progesterone insufficiency should not be a common cause of reproductive failure. Further evidence suggests that women with endometriosis, and possibly polycystic ovarian syndrome, have an altered progesterone response, which may explain some of the clinical features of these disorders and supports the hypothesis that progesterone resistance underlies some cases of human reproductive failure.

Dydrogesterone has a molecular structure closely related to that of natural progesterone, but it has enhanced oral availability compared with progesterone. The hormonal profile and the progestational potency of dydrogesterone has been determined in vitro, in vivo and in humans, in combination with estrogens or without. It showed varying affinity for progesterone-binding proteins in uterine tissue in vitro, depending on the species. It exerted a clear progestational response in the rabbit in vivo, although the potency was influenced somewhat by the route of administration. When used in hormone replacement therapy, 10mg dydrogesterone given sequentially provides adequate protection against endometrial hyperplasia in postmenopausal women using 2mg estradiol. Similarly, a dydrogesterone dose of 5mg also protects the endometrium when continuously combined with 1mg estradiol. Dydrogesterone also has beneficial effects in women with amenorrhea/oligomenorrhea, dysfunctional uterine bleeding and irregular cycles. In conclusion, having a similar profile to progesterone but with better oral availability, dydrogesterone has been used successfully to treat disorders related to absolute or relative progesterone deficiency., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

The incidence of low day 5 milk progesterone in dairy cows has been investigated and the efficacy of treating the problem assessed. The incidence of inadequate milk progesterone (empirically defined as <3ng/mL) in repeat breeder cows was 34% compared with 11.4% in first insemination cows. Treatment with an intravaginal progesterone device for 7 days starting from day 5 or 6 did not improve pregnancy rate. Treatment with 1500 iu human chorionic gonadotrophin (hCG) on day 5 gave an increase in pregnancy rate that was dependent on initial progesterone concentration and significant (P<0.05) in multiparous but not primiparous cows. While the incidence of inadequate day 5 progesterone was high in repeat breeder cows, it was responsive to hCG treatment, although only in multiparous and not primiparous animals.

Psychosomatics as a medical perspective and discipline focuses on the interaction of physical and mental health in a specific life situation of a patient, taking into account the physical and emotional wellbeing, role functioning, satisfaction with the partner and family relationship, as well as sexual function and satisfaction. The role of progesterone for the psychosomatic health of the climacteric woman depends on the individual symptom cluster and the pre-existing receptivity of the progesterone receptors which are widely distributed in the body and especially the brain of the woman. The complex action and interaction of progesterone is reflected in controversial empirical results about the impact of progesterone on the physical, mental and sexual health of climacteric women. From biological rationale and clinical experience there are however two important effects of P on the combined physical, mental and sexual wellbeing of climacteric patient: the antiestrogenic effect of progesterone is important on the peripheral physical level not only to protect the endometrium against overstimulation but also to reduce the individual suffering from heavy bleeding, breast tension, bloating and general discomfort. The positive anxiolytic and sedative effects of progesterone on the central nervous system depend on the type of progestogen, the dosage, the timing of application, the combination with estrogen etc. It can be concluded that progesterone and progestogens have an important potential to maintain or improve the psychosomatic health of the climacteric women. Their use must however be tailored to specific symptom clusters and to the individual's pre-existing psychosomatic health status.

Uteroplacental insufficiency in the rat reduces maternal progesterone and impairs mammary function and pup milk intake, compromising postnatal growth. We determined whether progesterone administration to rat dams progesterone-deficient following uteroplacental insufficiency improves lactation and pup growth. Uteroplacental insufficiency (Restriction) or sham surgery (Control) was performed on day 18 of pregnancy in WKY rats. Pregnant dams were injected with progesterone or vehicle, and Control mothers with vehicle for three days and killed on day 20 of pregnancy or day 6 of lactation. Progesterone treatment in the Restricted group restored maternal progesterone with no effect on mammary Pgr mRNA expression. Uteroplacental insufficiency triggered early lactogenesis, with increased mammary Csn2, Lalba and Wap mRNA. Progesterone treatment following uteroplacental insufficiency increased mammary alveolar number and area. Pups from progesterone treated mothers had increased body weight when compared to Controls. Overall, maternal progesterone treatment following uteroplacental insufficiency improved postnatal growth by rescuing the mammary impairment.

Fetal wastage has many causes, but genetic factors are by far the most common. The earlier the pregnancy loss occurs, the greater the likelihood of genetic causation. Among first trimester abortions, 50% to 80% show chromosomal abnormalities, usually aneuploidy. This is greater than all other causes combined. Chromosomal numerical abnormalities can be recurrent and sporadic; failure to take this into account is a major pitfall in many reports addressing causation. Moreover, many causes of fetal wastage that are traditionally considered to be "nongenetic" are actually the result of perturbations of gene products-proteins. Among nongenetic causes of first trimester fetal wastage, the best established are thyroid abnormities; antifetal antibodies; and the inherited and acquired thrombophilias. The latter are more established in the second trimester. Uterine anomalies can lead to second trimester losses. Infections seem uncommon, and alloimmune causes are not validated.

This study investigated placental expression of the two main isoforms of the progesterone receptor and the regulation of placental and fetal growth by progesterone over the final third of rat pregnancy, the period of maximal fetal growth. Expression patterns of mRNAs encoding the two major progesterone receptor isoforms (PR-A and PR-B) were measured by real-time RT-PCR in the two morphologically- and functionally-distinct regions of the placenta, the basal and labyrinth zones, at days 16 and 22 of pregnancy (term=day 23). PR-A and PR-B mRNA expression was extremely low in labyrinth zone on days 16 and 22, close to the limits of detection. In contrast, the basal zone exhibited much higher levels of mRNA expression for both PR-A (>10-fold higher than in labyrinth zone) and PR-B (3-fold higher at day 16). To assess the role of progesterone in placental growth, maternal progesterone was reduced from day 16 by ovariectomy with full estradiol replacement and partial progesterone replacement until day 22. Progesterone reduction lowered fetal (10%), whole placental (24%), basal zone (37%) and labyrinth zone (14%) weights at day 22 compared with sham-controls, whereas fetal and placental weights (both zones) were maintained in ovariectomised rats given full estradiol/progesterone replacement. The effects of progesterone withdrawal were not associated with changes in placental expression of either IGF-II or IGFBP-2, both important players in growth factor regulation of placental growth. Importantly, however, IGF-II expression remained elevated in the labyrinth zone but fell markedly in basal zone ( approximately 7-fold) between days 16 and 22 of normal pregnancy, consistent with the growth patterns of these two placental regions over this period.

Hypoluteoidism is characterized by insufficient secretion of progesterone by the corpora lutea during pregnancy. The resulting failure to maintain progesterone concentration above a critical level presumably could lead to fetal resorbtion as well as frank abortion. This report concerns a 2.5-year-old Bernese Mountain dog with a history of two previous pregnancies ending in abortion around Day 50 of pregnancy. The bitch was initially presented 2 days after mating. Physical and gynecological examination revealed no abnormalities. The infectious causes of abortion in the bitch, Brucella canis and herpesvirus, were excluded using serology. On Day 26 after mating, ultrasonography confirmed a pregnancy with at least four living fetuses. During the remaining part of the pregnancy repeated transabdominal ultrasonography and plasma progesterone measurements, using a RIA, were performed. On Day 42, ultrasonography revealed living fetuses but plasma progesterone concentration had decreased to 8.3 nmol/L, which is just above the threshold necessary to maintain a vital pregnancy. Oral treatment with 0.1mg medroxyprogesterone acetate (MPA) per kg body weight, once daily, was started and continued until Day 58 in order to prevent abortion due to progesterone deficiency. The endogenous plasma progesterone concentration decreased further, but pregnancy was maintained. On Day 59 a cesarean section was performed because of dystocia and four living and one dead pup were delivered. One puppy had severe facial malformations and was euthanised. The premature decrease in plasma progesterone concentration while ultrasonography demonstrated that the fetuses were still alive, and the maintenance of pregnancy during administration of MPA, strongly support the diagnosis of hypoluteoidism.

The causes of luteal phase progesterone deficiency in polycystic ovary syndrome (PCOS) are not known. To determine the possible involvement of hyperinsulinemia in luteal phase progesterone deficiency in women with PCOS, we examined the relationship between progesterone, luteinizing hormone (LH) and insulin during the luteal phase and studied the effect of metformin on luteal progesterone levels in PCOS. Patients with PCOS (19 women aged 18-35 years) were treated with metformin (500 mg three times daily) for 4 weeks prior to the test cycle and throughout the study period, and submitted to ovulation induction with clomiphene citrate. Blood samples were collected from control (N = 5, same age range as PCOS women) and PCOS women during the late follicular (one sample) and luteal (3 samples) phases and LH, insulin and progesterone concentrations were determined. Results were analyzed by one-way analysis of variance (ANOVA), Duncan's test and Karl Pearson's coefficient of correlation (r). The endocrine study showed low progesterone level (4.9 ng/ml) during luteal phase in the PCOS women as compared with control (21.6 ng/ml). A significant negative correlation was observed between insulin and progesterone (r = -0.60; P < 0.01) and between progesterone and LH (r = -0.56; P < 0.05) concentrations, and a positive correlation (r = 0.83; P < 0.001) was observed between LH and insulin. The study further demonstrated a significant enhancement in luteal progesterone concentration (16.97 ng/ml) in PCOS women treated with metformin. The results suggest that hyperinsulinemia/insulin resistance may be responsible for low progesterone levels during the luteal phase in PCOS. The luteal progesterone level may be enhanced in PCOS by decreasing insulin secretion with metformin.

Gonadotropin-primed immature rats (GPIR) constitute a widely used model for the study of ovulation. Although the equivalence between the ovulatory process in immature and adult rats is generally assumed, the morphological and functional characteristics of ovulation in immature rats have been scarcely considered. We describe herein the morphological aspects of the ovulatory process in GPIR and their response to classical ovulation inhibitors, such as the inhibitor of prostaglandin (PG) synthesis indomethacin (INDO) and a progesterone (P) receptor (PR) antagonist (RU486). Immature Wistar rats were primed with equine chorionic gonadotropin (eCG) at 21, 23 or 25 days of age, injected with human chorionic gonadotropin (hCG) 48 h later, and sacrificed 16 h after hCG treatment, to assess follicle rupture and ovulation. Surprisingly, GPIR showed age-related ovulatory defects close similar to those in adult rats lacking P and PG actions. Rats primed with eCG at 21 or 23 days of age showed abnormally ruptured corpora lutea in which the cumulus-oocyte complex (COC) was trapped or had been released to the ovarian interstitum, invading the ovarian stroma and blood and lymphatic vessels. Supplementation of immature rats with exogenous P and/or PG of the E series did not significantly inhibit abnormal follicle rupture. Otherwise, ovulatory defects were practically absent in rats primed with eCG at 25 days of age. GPIR treated with INDO showed the same ovulatory alterations than vehicle-treated ones, although affecting to a higher proportion of follicles. Blocking P actions with RU486 increased the number of COC trapped inside corpora lutea and decreased ovulation. The presence of ovulatory defects in GPIR, suggests that the capacity of the immature ovary to undergo the coordinate changes leading to effective ovulation is not fully established in Wistar rats primed with eCG before 25 days of age.

Endometrial carcinoma is listed under the absolute contraindications to hormone therapy (HT). According to current opinion, HT after stage I or II is still considered an option, and continuous combined oestrogen/progestogen replacement therapy (CCEPT) would be recommended. However, up to now, only observational studies have been put forward. Although none of these studies have established an increased rate of recurrence or mortality, alternatives such as phytopreparations and tibolone, or particular psychotherapeutic drugs, such as venlafaxine, should be considered for the relief of climacteric complaints. Progestogen-only therapy (PT) particularly has been considered. However, the currently discussed possible progestogen effects regarding an increased risk of breast cancer have to be taken into account. Indeed, the wider discussion about the gestagen effects regarding the risk of breast cancer is to be considered. Generally, after hysterectomy, at least for patients with cardiovascular risk factors, the preference today is to use low-dose oestrogen therapy (patches or gels) instead of CCEPT, and this is also now recommended for patients after endometrial cancer. This is to be noted because of the risk factors for endometrial carcinoma, such as hypertension, obesity, polycystic ovary syndrome (PCO) and diabetes mellitus. However, each form of HT should be only exceptionally recommended, and the patients must be informed about the risks that exist and the use of alternatives., (Copyright 2004 Society for Endocrinology)

In patients with distal tubal occlusion a microsurgical oviductal reconstruction is, apart from the in vitro fertilization, the only treatment option. Unfortunately, the results of reconstructive surgery are often unsatisfactory. The effects of sex steroids on the regeneration process after reconstructive surgery have not been well investigated. This study was aimed to evaluate the effect of decreased concentrations of ovarian sex steroids (castration) on regeneration of the oviduct mucosa after the reconstructive surgery of distally occluded oviducts. The study was performed on 32 female rabbits that underwent unilateral oviduct ligature and resection of fimbriae. The occlusion lasted six (group I) or twelve weeks (group II). After this time the animals were re-operated, and allocated into 4 groups: castration with reconstructive surgery (IA, IIA), reconstructive surgery only (IB, IIB). After next six or twelve weeks the fallopian tubes were examined under light, scanning and transmission electron microscopes. An immunohistochemical reaction for Ki-67 proliferative antigen was also performed. Ovarian steroid levels were evaluated by radioimmunoassays. The castrated animals had significantly lower levels of estradiol, progesterone and 17-hydroxyprogesterone than the control groups. Long lasting tubal occlusion caused pronounced histological changes of tubal mucous membrane (group II). In the rabbits with preserved ovaries and twelve-week long oviductal occlusion (group IIB), the regeneration of the distal end and restoration of fimbria were not complete twelve weeks after microsurgical reconstruction. In castrated animals with long-lasting occlusion (group IIA) the destructive changes, found in the mucosa of tubal ampullas of occluded oviducts before reconstruction, were still present and even intensified twelve weeks following reconstructive surgery. The castration hampered proliferation of the mucosa cells, thus no fimbriae were restored. Low levels of ovarian steroids were found to have adverse effect on fallopian tube regeneration following reconstructive surgery. The effect was noted even in cases with minor preoperative fallopian tube damage. Therefore, the treatment of concomitant endometriosis or uterine fibroids with GnRH analogues should not be recommended simultaneously with microsurgical tubal reconstruction.

In women with epilepsy, seizures can be influenced by variations in sex hormone secretion during the menstrual cycle. The proconvulsant effects of estrogen have been demonstrated in both animals and humans, whereas progesterone has been found to have anticonvulsant properties. Catamenial epilepsy affects approximately one-third of women with epilepsy. This type of epilepsy has generally been defined as an increase in seizure frequency beginning immediately before or during menses. However, three distinct patterns of catamenial epilepsy have been described: perimenstrual, periovulatory, and luteal. The diagnosis of catamenial epilepsy can be made through careful assessment of menstrual and seizure diaries and characterization of cycle type and duration. A variety of therapies for catamenial epilepsy have been proposed, including acetazolamide, cyclical use of benzodiazepines or conventional antiepileptic drugs (AEDs), and hormonal therapy. However, evidence for the effectiveness of these treatment approaches comes from small, unblinded series or anecdotal reports. Larger multicenter trials, as well as further investigation of the pathophysiology of the disorder, are needed to identify the most effective treatment for women with catamenial epilepsy.

As part of the timed breeding colony at Tulane National Primate Research Center, exogenous progesterone administration (5 mg/day for 10 days) has been used to select conception dates by inducing artificial luteal phases in female rhesus monkeys. A retrospective analysis of data obtained during four breeding seasons (1998-2001) revealed that conceptions occurred an average of 18 days after the last administration of progesterone. The age of the female to be bred, previous pregnancy history, and timing of breeding during the breeding season were determined to be critical factors in the success of the procedure. The benefit of this method of timed breeding is that it does not require tracking of menstrual cycles, which can be labor-intensive and requires that animals be monitored several months in advance of breeding to determine each female's individual cycle length. It also provided an efficient use of breeding-age males., (Copyright 2003 Wiley-Liss, Inc.)

The present in vitro autoradiography study demonstrates that prenatal exposure to morphine alters the density of mu-opioid receptors in the hippocampus of adult female but not adult male rats. Prenatal morphine exposure increased the mu-opioid receptor density in the CA1 of ovariectomized (OVX) females and in the CA3 of OVX, estradiol benzoate-plus progesterone (EB+P)-treated females, but decreased it in CA3 of OVX females. There were also hormonal effects on mu-opioid receptor density in adult female rats. In the CA1, only morphine-exposed but not saline-exposed, hormone-treated females (EB, P, or EB+P) had a decrease in mu-opioid receptor density relative to OVX females. Both saline-exposed and morphine-exposed, OVX females after gonadal hormone replacement had a lower density of mu-opioid receptors in the CA3 and in the dentate gyrus (DG) than OVX females. In male rats, there was a decrease in mu-opioid receptor density in the CA1 and CA3 of gonadectomized (GNX), testosterone 17beta-proprionate (TP)-treated males relative to GNX males regardless of prenatal morphine exposure. In the DG, the mu-opioid receptor density was reduced only in morphine-exposed but not in saline-exposed, TP-treated males compared with GNX males. Thus, our data demonstrate that mu-opioid receptor density in the hippocampus is affected by prenatal morphine exposure and by male and female gonadal hormones.

Purpose: The aim of this study was to investigate BMD in Danish female elite gymnasts and the relationships to maximal muscle strength, sex hormone concentrations, and menstrual status., Methods: Six artistic gymnasts, five rhythmic gymnasts, and six controls aged 15-20 yr served as subjects. BMD (g x cm(-2)) of lumbar spine, proximal femur, distal radius, and whole body were measured by dual-energy x-ray absorptiometry (DXA) scanning. Maximal muscle strength (Nm) was measured in isokinetic trunk extension, trunk flexion, and knee extension. Serum concentrations of estrogen and progesterone in follicular and luteal phases were evaluated., Results: Three out of six artistic gymnasts had amenorrhea, and two artistic and one rhythmic gymnast experienced oligomenorrhea. BMD in artistic gymnasts was greater than controls (24-45%, P < 0.05) in all sites except whole body. BMD in rhythmic gymnasts was greater than controls (4-26%, P < 0.05) in all sites except distal radius. In gymnasts, BMD correlated to both maximal muscle strength (0.60 < r < 0.85, P < 0.05) and serum progesterone (0.65 < r < 0.75, P < 0.05)., Conclusion: In spite of oligomenorrhea or amenorrhea, it is possible for female gymnasts to maintain a high BMD in both the axial (L2-L4) and appendicular skeleton. The correlations between BMD and maximal muscle strength and progesterone concentration in gymnasts may indicate that within the same athletic group, progesterone concentration has a permissive role in bone formation, thus affecting the positive impact of muscle strength.

In vivo fluctuations in gonadal hormones alter hippocampal excitability and modulate both physiological and pathological hippocampal processes. To assess hormonal effects on excitability within a functional hippocampal circuit, extracellular CA1 field responses were compared in slices from intact male, intact female, orchidectomized male, and ovariectomized female rats. Secondly, the effects of in vitro applications of 17-beta estradiol, progesterone, or testosterone on baseline excitability of slices from gonadectomized rats were assessed versus pre-hormone baseline measures. Finally, using the in vitro kindling model of slice epileptogenesis, steroid hormone effects on interictal-like activity were also examined. Significant sex differences in excitatory postsynaptic potential amplitude were observed, with slices from males having larger excitatory postsynaptic potential amplitudes than those from females. Gonadectomy significantly decreased excitatory postsynaptic potential amplitude in slices from male rats. Slices from gonadectomized male and female rats also showed a decreased dendritic excitatory postsynaptic potential slope relative to slices from intact male and females rats. In vitro application of testosterone significantly increased excitatory postsynaptic potential amplitudes in slices from both orchidectomized males and ovariectomized females and the population spike amplitude of slices from ovariectomized females. Following in vitro kindling, slices from intact males showed greater spontaneous burst rates than slices from intact females, further suggesting an excitatory effect of testosterone. These results suggest: (1) a sex difference in the level of baseline excitability between slices from intact males and females as measured by excitatory postsynaptic potential amplitudes, (2) testosterone has excitatory effects on baseline physiology and kindled hippocampal responses, and (3) slices from males show a greater level of excitability than those from females in the in vitro kindling model.

In examining 502 female patients with cancer of the ovaries (OC) infertility was identified in 21.9 percent of cases. The prevalent form of infertility was tubal infertility (92.7%), there were but a few instances of the endocrine form (1.8%). The infertile women were studied for their hormonal and receptorial status (receptors of estradiol and progesterone). It has been established that women with the endocrine variant of infertility present with more prominent hormonal inadequacies in the hypophysis-ovaries system and manifest changes in the receptorial status of the ovaries than those with tubal infertility; the findings in the latter have not been shown to be different from controls. In endocrine infertility OC is in fact not encountered, which fact can be related to morphological features of the ovaries giving origin to endocrine disturbances, and to a decline in the receptorial status and absence of ovulation.

Four separate components combine to produce the progesterone and biologically active 5 alpha-reduced pregnanes needed to maintain pregnancy in the mare. The primary corpus luteum (CL) is prolonged beyond its cyclical lifespan by the down-regulation of endometrial oxytocin receptors to prevent activation of the luteolytic pathway and its waning progesterone production is supplemented from day 40 of gestation by the formation of a series of accessory CL which develop in the maternal ovaries as a result of the gonadotrophic actions of pituitary FSH and the equine chorionic gonadotrophin (eCG). From around day 100 the allantochorion secretes progesterone and progestagens directly to the endometrium and underlying myometrium and, in the last month of gestation, the enlarging foetal adrenal gland secretes appreciable quantities of pregnenelone which is also utilized by the placenta to synthesize progestagens. Between 10 and 15% of mares undergo foetal death and abortion at some time in gestation and the majority of these losses occur during the first 40 days of gestation when the primary CL is the sole source of progesterone. Yet, all the available evidence suggests that untoward luteolysis is not common in this period and the losses that do occur have other underlying causes. Beyond day 40 the secondary CL receive powerful luteotrophic support from eCG and from day 80-100 until term the supply organ (placenta) and target tissues (endometrium and myometrium) are in direct contact with each other over their entire surface. In the face of this interlocking and failsafe system for progestagen production throughout pregnancy, and despite a paucity of evidence that a deficiency of progesterone production is a cause of pregnancy loss in the mare, it is surprising, and worrying, that annually many thousands of pregnant mares throughout the world are given exogenous progestagen therapy during part or all of their gestation as a form of preventative insurance against the possibility of pregnancy failure. Basic investigative research is required urgently to validate or debunk the practice.

Previous in vivo findings show that in the virtual absence of progesterone (P), the antiprogestin RU486 reduces LH and FSH secretion in proestrous rats, indicating that activation of P receptor (PR) can occur in the absence of the cognate ligand. The present study investigates, in vitro, whether or not the inhibitory effect of antiprogestin RU486 on gonadotropin secretion in the absence of P is estrous cycle dependent, and whether its specific expression in proestrus mirrors the high estrogen (E2) background. In the first experiment we investigated the effect of RU486 (10 nM) and/or LHRH (10 nM) on LH and FSH secretion in incubated pituitaries collected on each day of the estrous cycle of the rat. In the second experiment, we determined the effect of RU486 and/or LHRH on preovulatory LH and FSH release by pituitaries from female rats that were ovariectomized (OVX), treated with the antiestrogen LY117018-HCL (Eli Lilly & Co.), or injected with 20 micrograms of estradiol benzoate (EB). The third experiment investigated the effect of RU486 and/or LHRH on LH and FSH release by pituitaries collected from intact or EB-treated (0.1 mg/kg over three consecutive days) male rats. RU486 reduced both basal and LHRH-stimulated LH and FSH secretion in proestrous pituitaries from normal 4-day cyclic rats. By contrast, in diestrous pituitaries, RU486 increased both parameters of LH secretion but was without effect on FSH release. RU486 was also without effect in pituitaries collected from rats in estrus or metestrus, or from OVX or antiestrogen-treated rats. Moreover, EB injection or treatment induced the full inhibitory effect of RU486 in pituitaries from female and male rats, respectively. The above results suggested that P occupancy of the receptor is not required for the formation or function of the active receptor and hence for preovulatory LH and FSH secretion, and that this form of PR activation at pituitary level is E2-dependent and not genetically determined.

Background and Purpose: We have previously shown that female animals experience substantial protection from brain injury after reversible middle cerebral artery occlusion (MCAO) compared with their male or ovariectomized female counterparts. The reproductive steroid estrogen has been shown to provide neuroprotection from a variety of experimental insults, but the importance of progesterone as an anti-ischemic treatment has not been well explored. We evaluated histological outcomes after MCAO in ovariectomized female rats with or without acute or chronic progesterone replacement therapy., Methods: Age-matched, adult female Wistar rats were ovariectomized and treated with 0, 30, or 60 mg/kg progesterone IP 30 minutes before ischemia (n=12 to 14 per group) or with 30 mg/kg progesterone IP daily for 7 to 10 days before ischemia (n=16). Each animal subsequently underwent 2 hours of MCAO with the intraluminal filament technique, followed by 22 hours of reperfusion. Ipsilateral parietal cortex perfusion was monitored with laser Doppler flowmetry throughout ischemia. Cortical, caudate-putamen, and hemispheric infarction volumes were determined with 2,3,5-triphenyltetrazolium chloride staining and digital image analysis., Results: Intraischemic plasma progesterone levels were 5+/-3, 102+/-20,* 181+/-28,* and 133+/-25* ng/mL in the 0, 30, and 60 mg/kg acute progesterone group and the 30 mg/kg chronic progesterone group, respectively (*P<0.05 compared with 0 mg/kg). Caudate-putamen infarction volume (percent contralateral structure) was significantly increased by chronic progesterone treatment: 45.6+/-5.1%* in the 30 mg/kg chronic progesterone group and 29.2+/-5.3%, 35.8+/-5.1%, and 42.0+/-5.0% in the 0, 30, and 60 mg/kg acute progesterone groups, respectively (*P<0.05 compared with 0 mg/kg). Cortical and total hemispheric infarction volumes (percent contralateral structure) were unchanged by progesterone treatment., Conclusions: Exogenous progesterone therapy does not ameliorate histological injury after MCAO in previously ovariectomized, adult female rats. Furthermore, chronic progesterone administration can exacerbate infarction in subcortical regions.

The importance of epidermal growth factor (EGF) in both normal and malignant mammary gland development are presented in these studies. Initial findings demonstrated that in the absence of ovarian hormones, EGF had a significant proliferative effect on mammary epithelial cells. To determine whether mammary epithelial cells grown with EGF, in the absence of ovarian hormones, could be transformed by N-methyl-N-nitrosourea (MNU), female ovariectomized Lewis rats were implanted with pellets containing EGF for 1 week and then treated with MNU for initiation. Two days after MNU treatment, ovaries were implanted and EGF pellets were removed from all ovariectomized groups in order to promote carcinogenesis. The mammary carcinoma incidence of the EGF-stimulated group (90%) was not significantly different from the intact group (100%). The mammary cancer morphology of EGF-treated carcinomas was either ductal carcinoma or cribriform adenocarcinoma, whereas intact animals developed mainly papillary and occasional cribriform carcinomas. Fifty-eight percent of the carcinomas from the EGF group were ovarian hormone-independent compared with 10% of carcinomas from the intact group. These results demonstrate that EGF-induced proliferation during initiation with MNU was sufficient to induce the transformation of mammary carcinomas in the absence of ovarian hormones. The hormonal dependency of these EGF-induced carcinomas were different compared with MNU-initiated mammary carcinomas in intact rats.

Cytohormonal profile of unstained vaginal smears were studied under phase contrast microscope to define various cell morphologies in detail and build up of smear pattern serially in various stages of menstrual cycle and first trimester of pregnancy. The findings were correlated clinically and found comparable to Papanicolaou stained smears. The maturation index was calculated more objectively by phase contract microscopy because of the refractile appearance of the pyknotic nuclei of superficial cells. The prognostication of abortion was done by combining abnormal maturation index and the presence of syncytiotrophoblasts in vaginal smears. Under phase contrast microscope, the sensitivity of abnormal smear was 87.5%, the specificity was 95%, the positive predictive value was 96.55% and the overall accuracy was 90% as compared to positive Papanicolaou smear whose sensitivity though 93%, had low specificity of 50% only. Phase contrast study appears to offer certain distinct advantage over the conventional light microscopy for quick, comprehensive and quantitative assessment of the study material. It allows the physician to detect changes in the material obtained from the patients without detour of laboratory fixation and staining. It is technically easy as errors in interpretation due to unsatisfactory fixation, staining and artefacts are obviated. Thus phase contrast microscopy offers an alternative and easy method of cytohormonal evaluation of wet and unstained smears.

Objective: To determine whether serum inhibin A and inhibin B concentrations are lower in patients with luteal dysfunction than in women with normal luteal function., Methods: Serum samples were collected from seven healthy women with regular menstrual cycles. Serum samples on days +5 to +9 after the LH surge were collected from patients with luteal dysfunction. The diagnosis of luteal dysfunction was based on a luteal phase duration less than 11 days and a single midluteal progesterone level below 10 ng/mL. Serum levels of inhibin A, inhibin B, progesterone, estradiol (E2), FSH, and LH were measured., Results: The serum inhibin A levels were increased toward the late follicular phase. The levels reached a maximum during the midluteal phase, followed by a fall during the late luteal phase. The serum inhibin B levels were high during the follicular phases and the early luteal phase. The levels decreased during the midluteal and late luteal phases. Serum levels (mean +/- standard error of the mean) of inhibin A in patients with luteal dysfunction were significantly lower than those in women during the midluteal phase (26.2 +/- 2.9 compared to 41.9 +/- 2.8 pg/mL; P < .01) in addition to the expected decrease in serum progesterone levels (6.3 +/- 0.7 compared to 14.7 +/- 1.2 ng/mL; P < .01). Serum inhibin B levels did not differ significantly between normal women and those with luteal dysfunction. There also were no significant differences in the E2, FSH, and LH levels., Conclusion: Levels of inhibin A, but not of inhibin B, may reflect the human luteal function.

The aetiology of polycystic ovary syndrome (PCOS) is unknown. It is uniquely characterized by oligomenorrhoea or amenorrhoea associated with normal or high oestrogen levels. This prospective clinical study was designed to examine the possible role of the lack of cyclical exposure to progesterone in the development of gonadotrophin and androgen abnormalities in PCOS. Gonadotrophin, androgen and oestrogen levels were measured in 15 PCOS patients and 10 normal subjects untreated and following treatment with the progestogen medroxyprogesterone acetate (MPA). When compared to control subjects, PCOS patients had significantly higher luteinizing hormone (LH) pulse height, pulse amplitude, integrated LH levels, LH response to gonadotrophin-releasing hormone (GnRH) and LH/FSH ratio; LH pulse frequency was similar in the two groups. In addition, the testosterone/sex hormone binding globulin ratio (T/SHBG), androstenedione and oestrone concentrations in the plasma were significantly higher in PCOS than in control subjects. When PCOS patients were treated with MPA for 5 days, there were significant decreases (p < 0.02-0.001) to values no longer different from normal: from 8.7 +/- 1.2 to 5.6 +/- 0.8 IU/l for integrated LH levels (untreated and MPA-treated PCOS); from 31.2 +/- 3.5 to 12.9 +/- 1.5 IU/l for LH response to GnRH; from 2.4 +/- 0.26 to 1.3 +/- 0.2 for LH/FSH ratio; and from 10.4 +/- 0.63 to 8.5 +/- 0.7 nmol/l for androstenedione. Significant decreases (p < 0.05-0.005) to values that still remained significantly higher than in normal subjects occurred for: LH pulse height, 11.05 +/- 1.3 to 6.88 +/- 0.79 IU/l (untreated and MPA-treated PCOS); LH pulse amplitude, 2.8 +/- 0.5 to 1.8 +/- 0.2 IU/l; total testosterone, 2.5 +/- 0.2 to 2.0 +/- 0.2 nmol/l; T/SHBG ratio, 14.1 +/- 1.7 to 11 +/- 1.5; and oestrone, 265 +/- 24 to 208 +/- 29 pmol/l. These results are consistent with the concept that ovulation failure and progesterone deficiency play a facilitatory role in the development of the hypothalamic-pituitary abnormality giving rise to disordered LH secretion in PCOS.

The time course of the behaviour of GABAA receptors (affinity of muscimol for GABA binding sites and their number) in membranes obtained from five distinct rat brain areas was evaluated in dependence of the decline of the serum concentrations of estradiol and progesterone following hormone deprivation by either ovariectomy (OVX) or ovary- plus adrenalectomy (OVX-ADX) after 1, 2, 3, 5, 14 and 30 days. Diestrus rats served as control. The effect of OVX on the GABA binding sites was due to a decrease of affinity rather than alterations in their density. Conversely, the combined surgery of OVX plus ADX affected both the affinity and the density. Also, the OVX-linked changes of muscimol binding were observed only after five days as compared to control animals, while the initial OVX-ADX associated changes occurred already after one day. OVX-ADX produced significant decreases in the number of binding sites at the shortest times investigated, in frontal cortex (FC) at day one and two and in the medulla oblongata (MED) after three days, which disappeared in the subsequent times studied. Concomitant with the major decrease of steroid hormone serum levels one day after OVX-ADX the FC displayed an increase in affinity by 45%. From the time when steroid serum levels are low the alterations in affinity elicited by both OVX-ADX and OVX only take a similar course, reflected by the following decrease in affinity. In MED an additional adrenalectomy did not significantly modify the OVX linked decrease of affinity, except that the initial effect was already evident two days after OVX-ADX.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To determine the incidence of both isolated and repetitive prolactin elevations in the luteal phase of otherwise normoprolactinemic women. To see if sporadic luteal-phase hyperprolactinemia is associated with progesterone deficiency, and to explore a possible physiological basis for sporadic hyperprolactinemia by TRH challenge., Setting: Hospital-based reproductive endocrinology/infertility service., Design: Prospective measurement of luteal phase serum progesterone and prolactin in normoprolactinemic ovulatory women. TRH stimulation testing in volunteers with repetitive luteal phase hyperprolactinemia and normoprolactinemic controls., Patients: 133 sequentially selected infertile, ovulatory women with normal prolactin levels in the proliferative phase of the cycle., Interventions: Measurement of serum progesterone and prolactin during the luteal phase, based on the day of the LH surge. TRH testing in the midluteal phase of the cycle in patients with two or more luteal phase prolactin elevations, and in five normoprolactinemic volunteers in both the preovulatory and midluteal phase., Results: Of 133 subjects, 85 (64%) had no prolactin level exceeding 20 ng/mL in the luteal phase. Thirty-three (25%) had two or more elevated levels, and were considered to have repetitive luteal phase hyperprolactinemia (LPH). TRH testing in control subjects resulted in a greater prolactin response in the preovulatory phase. The group with LPH demonstrated an initial elevation of prolactin greater than that of the normoprolactinemic controls, but a subsequent drop to levels lower than both preovulatory and midluteal normoprolactinemic controls by 45 minutes., Conclusions: Sporadic luteal-phase hyperprolactinemia is a relatively common event (36% of 133 subjects in the present series). Of these 48 women, 33 (69%) had repetitive elevations, suggesting the elevation in these subjects to be more than a random event. The physiological validity of this observation is further demonstrated by an abnormal response to TRH stimulation, but the normal levels of luteal phase progesterone leave questions as to its pathological importance.

A 13 year old girl referred for chromosome analysis because of disproportionate short stature (short neck, curved legs, pectus excavatum) with an initial clinical diagnosis of Turner's syndrome was found to have the karyotype 46,X, + der(X) in 100% of her blood lymphocytes. By means of conventional differential staining (QFH/AcD, FPG, and RBA banding) supplemented with distamycin A treatment, the karyotype of the proband was interpreted as 46,X,t(X;Y) (p22.3;q11). The rearranged marker X chromosome was found to be active in 91% of lymphocytes studied. PCR analysis with Y chromosome specific oligoprimers showed the presence of some Y chromosome long arm DNA in both lymphocyte and gonadal tissue biopsy cells. At laparoscopy the patient was found to have small gonads with a rudimentary uterus and fallopian tubes. Histological examination of gonadal tissue showed primary follicles with dystrophic changes of the germ cells and numerous follicular cysts (polycystic ovaries). The proband's phenotype and its correlation with the genetic imbalance of the rearranged X chromosomes, as well as with non-random t(X;Y) chromosome inactivation, are briefly discussed.

It has been reported that there exists a correlation between endometriosis and the luteal phase defect (LPD) as one of the determinants in infertility. In some theories, the hampered maturation of the corpus luteum is believed to be caused by the reduction of LH receptors, increase in prolactin, prostaglandin and macrophages in endometriosis. The purpose of this clinical study is to prove the hypothesis that there exists a significant correlation between endometriosis and the luteal phase defects in infertility. The samples were taken at random from 150 women with infertile marriages on whom ovulation was assumed to have occurred, from January 1981 to December 1985. The assumption that there might have occurred ovulation is determined through the observation of their basal body temperature (BBT) chart. Endometrium biopsies to diagnose the LPD were taken at the end of their luteal phase. A laparoscopy examination to diagnose the pelvic endometriosis was done in the following cycle. Of 84 patients with endometriosis, 44 (55.4%) had luteal phase defects, while the remaining 40 (47.6%) patients had no luteal phase defects. Of the 66 patients without endometriosis, 27 (40.9%) had luteal phase defects, while the remaining 39 (59.1%) did not have luteal phase defects. These differences were not significant (p > 0.05). In summary, this clinical study fails to show the existence of significant correlation between endometriosis and the luteal phase defect.

Fourteen infertile women and two women with recurrent abortions were suspected of having luteal phase defect (LPD) by BBT charts. In these patients, the midluteal phase serum progesterone (P) levels were determined together with histological examination by the late luteal endometrial biopsies during the same cycle. The diagnostic criteria for LPD was BBT of luteal phase < or = eleven days, mean P level of 3 blood samples taken on three days during midluteal phase was less than 48 nmol/L (15 ng/ml) and the histological dating of endometrium was two or more days behind. The results showed that histological abnormality and low P level were 6.3% and 31.3%, respectively. When histological abnormality combined with lowered P level at the same cycle, the diagnosis of LPD increased to 87.5%. The author suggests that both midluteal phase P level and late luteal endometrial histological examination should be assessed at the same cycle in the diagnosis of LPD. BBT should also be assessed.

Oestrogen deficiency is the main physiopathological factor of postmenopausal osteoporosis. The repercussions on bone metabolism of decrease in other sex steroid levels (progesterone, androgens) remains imperfectly known. Several studies on both animals and man have demonstrated that androgens and progestogens derived from testosterone have an anabolic effect on bone tissue. The latest data from studies conducted in non-menopausal women treated with progesterone suggest that this hormone might prevent bone loss. The mechanism of action of this effect on cells remain to be determined, even though progesterone has been shown to exert a mitogenic activity in vitro. Altogether, these data suggest that side by side with oestrogen deficiency the decrease of other sex steroid levels might also play a role in the physiopathology of postmenopausal bone loss.

Objective: To determine if reductions in plasma progesterone (P) secretion seen in luteal phase deficiency (LPD) might be because of reduced availability of circulating low-density lipoprotein (LDL) or high-density lipoprotein (HDL), known substrates for corpus luteum P synthesis., Design: We measured plasma lipoproteins in the luteal phase of the menstrual cycle in 39 infertile women. These women were divided into two groups on the basis of endometrial biopsies; the LPD group had biopsies that were greater than or equal to 3 days out-of-phase., Setting: All participants were recruited from the Reproductive Endocrinology and Infertility Clinic at the University of Washington, an institutional tertiary care center., Patients, Participants: Eighteen women had in-phase and 21 had out-of-phase LPD biopsies., Main Outcome Measure: Lipoprotein levels were obtained in a fasted state on the day of the luteal phase on which the biopsy was performed., Results: No difference in covariates that affect lipoprotein levels such as obesity, age, and alcohol use were observed between the two groups. No significant differences between groups were found for triglycerides, total cholesterol, very low density lipoprotein, LDL, HDL, HDL2, and HDL3 concentrations. However, LPD was associated with a reduction in the extent to which: age and obesity are associated with higher triglycerides; obesity is associated with a lower HDL2; and alcohol is associated with a higher HDL3-cholesterol., Conclusions: Lipoproteins on average are not different in LPD, suggesting reasons other than a deficient plasma lipoprotein cholesterol source as the explanation for decreased P secretion. A lesser interaction between LDL or HDL and obesity, age, and alcohol in LPD could signify an influence of the altered hormonal milieu of LPD on the way lipoproteins interact with covariates and could lead to differences in lipoproteins between normal and LPD subjects at the extremes of the lipoprotein distribution.

The role of decreased luteal activity in embryonic loss after induced endotoxemia was studied in mares 21 to 35 days pregnant. Fourteen pregnant mares were treated daily with 44 mg of altrenogest to compensate for the loss of endogenous progesterone secretion caused by prostaglandin F2 alpha (PGF2 alpha) synthesis and release following intravenous administration of Salmonella typhimurium endotoxin. Altrenogest was administered daily from the day of endotoxin injection until day 40 of gestation (group 1; n = 7), until day 70 (group 2; n = 5), or until day 50 (group 3; n = 2). In all mares, secretion of PGF2 alpha, as determined by the plasma 15-keto-13,14-dihydro-PGF2 alpha concentrations, followed a biphasic pattern, with an initial peak at 30 minutes followed by a second, larger peak at 105 minutes after endotoxin injection. Plasma progesterone concentrations decreased in all mares to values less than 1 ng/ml within 24 hours after endotoxin injection. In group 1, progesterone concentrations for all mares were less than 1 ng/ml until the final day of altrenogest treatment. In 6 of 7 mares in group 1, the fetuses died within 4 days after the end of treatment, with progesterone concentrations less than 1 ng/ml at that time. In the mare that remained pregnant after the end of treatment, plasma progesterone concentration was 1.6 ng/ml on day 41 and increased to 4.4 ng/ml on day 44. In group 2, all mares remained pregnant, even though plasma progesterone concentrations were less than 1 ng/ml in 4 of 5 mares from the day after endotoxin injection until after the end of altrenogest treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors followed 187 pregnancies in which metrorrhagia had occurred in the first trimester, but which had not resulted in abortion. In these patients, the authors studied particularly changes in hormone levels in the urine and the relation between these levels and fetal prognosis. If hormonal deficit is related to fetal prognosis, the relationship does not appear to be a direct one: estrogen deficiency is discovered more often than luteal deficiency; the more serious the estrogen deficiency the more often is it associated with severe progesterone deficiency; The number of fetal malformations did not seem to be any higher in patients who had presented metrorrhagia in first trimester than in patients whose pregnancy was normal. Any higher in patients who had presented metrorrhagia in the pregnancy on one hormone analysis, whether or not it is abnormal. The examinations should be repeated so that the evolution may be followed carefully.