Ovarian Steroid Levels Research Articles

Ovarian steroids regulate tachykinin and tachykinin receptor gene expression in the mouse uterus

BackgroundIn the mouse uterus, pregnancy is accompanied by changes in tachykinin and tachykinin receptor gene expression and in the uterotonic effects of endogenous tachykinins. In this study we have investigated whether changes in tachykinin expression and responses are a result of changes in ovarian steroid levels.MethodsWe quantified the mRNAs of tachykinins and tachykinin receptors in uteri from ovariectomized mice and studied their regulation in response to estrogen and progesterone using real-time quantitative RT-PCR. Early (3 h) and late (24 h) responses to estrogen were evaluated and the participation of the estrogen receptors (ER), ERalpha and ERbeta, was analyzed by treating mice with propylpyrazole triol, a selective ERalpha agonist, or diarylpropionitrile, a selective agonist of ERbeta.ResultsAll genes encoding tachykinins (Tac1, Tac2 and Tac4) and tachykinin receptors (Tacr1, Tacr2 and Tacr3) were expressed in uteri from ovariectomized mice. Estrogen increased Tac1 and Tacr1 mRNA after 3 h and decreased Tac1 and Tac4 expression after 24 h. Tac2 and Tacr3 mRNA levels were decreased by estrogen at both 3 and 24 h. Most effects of estrogen were also observed in animals treated with propylpyrazole triol. Progesterone treatment increased the levels of Tac2.ConclusionThese results show that the expression of tachykinins and their receptors in the mouse uterus is tightly and differentially regulated by ovarian steroids. Estrogen effects are mainly mediated by ERalpha supporting an essential role for this estrogen receptor in the regulation of the tachykinergic system in the mouse uterus.

Ovarian‐Steroid Modulation of Locus Coeruleus Activity in Female Rats: Involvement in Luteinising Hormone Regulation

The noradrenergic nucleus locus coeruleus (LC) has been reported to regulate luteinising hormone (LH) secretion in female rats. Both oestrogen and progestin receptors have been demonstrated in LC neurones, suggesting that these cells are possibly responsive to variations in circulating levels of ovarian steroids. We therefore evaluated changes in the activity of LC neurones during the oestrous cycle and after ovarian-steroid treatment in ovariectomised (OVX) rats, as determined by immunoreactivity to Fos-related antigens (FRA), which comprises all of the known members of the Fos family. Effects of ovarian steroids on the firing rate of LC neurones were also determined in a slice preparation. The number of FRA/tyrosine hydroxylase (TH)-immunoreactive (ir) neurones in the LC increased from 14.00-16.00 h on pro-oestrus, coinciding with the onset of the LH surge and rise in plasma progesterone. FRA immunoreactivity was unaltered during dioestrus. Oestradiol-treated OVX rats (OVX+E) displayed marked reduction in FRA/TH-ir neurones in LC compared to oil-treated OVX rats. Accordingly, oestradiol superfusion significantly reduced the spontaneous firing rate of LC neurones in slices from OVX rats. Compared to OVX+E, oestradiol-treated rats injected with progesterone at 08.00 h (OVX+EP) exhibited higher number of FRA/TH-ir neurones in the LC at 10.00 h and 16.00 h, and great amplification of the LH surge. Bath application of progesterone significantly increased the spontaneous firing rate of OVX+E LC neurones. Our data suggest that ovarian steroids may physiologically modulate the activity of LC neurones in females, with possible implications for LH secretion. Moreover, oestradiol and progesterone appear to exert opposite and complementary effects (i.e. whereas oestradiol inhibits, progesterone, after oestradiol priming, stimulates LC activity).

Ovarian steroids alter mu opioid receptor trafficking in hippocampal parvalbumin GABAergic interneurons

The endogenous hippocampal opioid systems are implicated in learning associated with drug use. Recently, we showed that ovarian hormones regulate enkephalin levels in the mossy fiber pathway. This pathway overlaps with parvalbumin (PARV)-basket interneurons that contain the enkephalin-activated mu opioid receptors (MORs) and are important for controlling the “temporal timing” of granule cells. Here, we evaluated the influence of ovarian steroids on the trafficking of MORs in PARV interneurons. Two groups of female rats were analyzed: cycling rats in proestrus (relatively high estrogens) or diestrus; and ovariectomized rats euthanized 6, 24 or 72 h after estradiol benzoate (10 μg, s.c.) administration. Dorsal hippocampal sections were dually immunolabeled for MOR and PARV and examined by light and electron microscopy. As in males, in females MOR-immunoreactivity (-ir) was in numerous PARV-labeled perikarya, dendrites and terminals in the dentate hilar region. Variation in ovarian steroid levels altered the subcellular distribution of MORs in PARV-labeled dendrites but not terminals. In normal cycling rats, MOR-gold particles on the plasma membrane of small PARV-labeled dendrites (area < 1 μm 2) had higher density in proestrus rats than in diestrus rats. Likewise, in ovariectomized rats MORs showed higher density on the plasma membrane of small PARV-labeled dendrites 72 h after estradiol exposure. The number of PARV-labeled cells was not affected by estrous cycle phase or estrogen levels. These results demonstrate that estrogen levels positively regulate the availability of MORs on GABAergic interneurons in the dentate gyrus, suggesting cooperative interaction between opioids and estrogens in modulating principal cell excitability.

Relative in vitro seasonal effects of vasotocin and isotocin on ovarian steroid hormone levels in the catfish Heteropneustes fossilis

In the present investigation, catfish ( Heteropneustes fossilis) ovarian tissues were incubated in vitro with vasotocin (VT) or isotocin (IT) to demonstrate their effects on estradiol-17β (E 2), progesterone (P 4), 17α-hydroxy-4-pregnene-3, 20-dione (17-P) and 17α, 20β-hydroxy-4-pregnen-3-one (17, 20β-DP). Parallel incubations with human chorionic gonadotropin (hCG) alone or in combination with VT were used for a comparison. In pre-vitellogenic phase (preparatory phase, GSI—0.48 ± 0.03%), both VT and hCG stimulated E 2 significantly, VT in a biphasic manner and hCG in a dose-dependent manner. In pre-spawning (post-vitellogenic, GSI—9.05 ± 0.11%) and spawning (post-vitellogenic, GSI—8.01 ± 0.12%) phases, both hormones decreased E 2 levels in a dose- and duration-dependent manner; the VT effect being biphasic in the spawning phase. The co-incubation with VT + hCG stimulated E 2 in the preparatory phase but inhibited it in the pre-spawning and spawning phases. The incubations with VT or hCG increased P 4 levels in a dose- and duration-dependent manner, the magnitude of the effect was higher in the pre-spawning and spawning phases. The co-incubation with VT + hCG stimulated P 4 without any additive effect. The P 4 derivatives (17-P and 17, 20β-DP) showed similar changes except 17-P in the spawning phase which decreased at 16 h of the incubation. The incubations with IT produced similar but low responses. In conclusion, like hCG, VT has differential effects on ovarian steroidogenesis and may be involved directly or indirectly in ovarian functions, as a paracrine/autocrine factor or a neurohormone.

Vascular Endothelial Growth Factor-A (VEGF-A) Single Nucleotide Polymorphisms and Endometriosis: Still a Controversial Issue

Endometriosis is a chronic, multifactorial, polygenic gynecological disease. Endometrium has a high angiogenic potential and endometriotic lesions involve large areas with a rich blood supply. Angiogenesis is controlled by numerous inducers, including the vascular endothelial growth factor (VEGF) family. Endometrium undergoes cyclical growth and regression during the menstrual cycle, which depends on ovarian steroid levels and is a rich source of angiogenic growth factors, including VEGF-A. The VEGF-A gene is located on chromosome 6p21.3 and it is highly polymorphic with more than 20 different variants. This article critically reviews the published data concerning the relationships between some of the VEGF-A single nucleotide polymorphisms and the risk, pathogenesis and stage of endometriosis. Contrasting results have been published in the literature - probably due to the different ethnic background and the number of patients enrolled in clinical trials. However, the increasing interest in the use of antiangiogenic drugs (eg anti-VEGF-A drugs) in the therapy of endometriosis may suggest carrying out further genetic and pharmacogenetic studies of this disease because the stratification of patients at risk of endometriosis can lead to early diagnosis and optimal treatment choice.

Hair Loss in Women

Female pattern hair loss (FPHL) is a clinical problem that is becoming more common in women. Female alopecia with androgen increase is called female androgenetic alopecia (FAGA) and without androgen increase is called female pattern hair loss. The clinical picture of typical FAGA begins with a specific "diffuse loss of hair from the parietal or frontovertical areas with an intact frontal hairline." Ludwig called this process "rarefaction." In Ludwig's classification of hair loss in women, progressive type of FAGA, 3 patterns were described: grade I or minimal, grade II or moderate, and grade III or severe. Ludwig also described female androgenetic alopecia with male pattern (FAGA.M) that should be subclassified according to Ebling's or Hamilton-Norwood's classification. FAGA.M may be present in 4 conditions: persistent adrenarche syndrome, alopecia caused by an adrenal or an ovarian tumor, posthysterectomy, and as an involutive alopecia. A more recent classification (Olsen's classification of FPHL) proposes 2 types: early- and late-onset with or without excess of androgens in each. The diagnosis of FPHL is made by clinical history, clinical examination, wash test, dermoscopy, trichoscan, trichograms and laboratory test, especially androgenic determinations. Topical treatment of FPHL is with minoxidil, 2-5% twice daily. When FPHL is associated with high levels of androgens, systemic antiandrogenic therapy is needed. Persistent adrenarche syndrome (adrenal SAHA) and alopecia of adrenal hyperandrogenism is treated with adrenal suppression and antiandrogens. Adrenal suppression is achieved with glucocorticosteroids. Antiandrogens therapy includes cyproterone acetate, drospirenone, spironolactone, flutamide, and finasteride. Excess release of ovarian androgens (ovarian SAHA) and alopecia of ovarian hyperandrogenism is treated with ovarian suppression and antiandrogens. Ovarian suppression includes the use of contraceptives containing an estrogen, ethinylestradiol, and a progestogen. Antiandrogens such as cyproterone acetate, always accompanied by tricyclic contraceptives, are the best choice of antiandrogens to use in patients with FPHL. Gonadotropin-releasing hormone agonists such as leuprolide acetate suppress pituitary and gonadal function through a reduction in luteinizing hormone and follicle-stimulating hormone levels. Subsequently, ovarian steroid levels also will be reduced, especially in patients with polycystic ovary syndrome. When polycystic ovary syndrome is associated with insulin resistance, metformin must be considered as treatment. Hyperprolactinemic SAHA and alopecia of pituitary hyperandrogenism should be treated with bromocriptine or cabergoline. Postmenopausal alopecia, with previous high levels of androgens or with prostatic-specific antigen greater than 0.04 ng/mL, improves with finasteride or dutasteride. Although we do not know the reason, postmenopausal alopecia in normoandrogenic women also improves with finasteride or dutasteride at a dose of 2.5 mg per day. Dermatocosmetic concealment with a hairpiece, hair prosthesis as extensions, or partial hairpieces can be useful. Lastly, weight loss undoubtedly improves hair loss in hyperandrogenic women.

New Aspects for the Treatment of Cardiac Diseases Based on the Diversity of Functional Controls on Cardiac Muscles: Acute Effects of Female Hormones on Cardiac Ion Channels and Cardiac Repolarization

Regulation of cardiac ion channels by sex hormones accounts for gender differences in susceptibility to arrhythmias associated with QT prolongation (TdP). Women are more prone to develop TdP than men with either congenital or acquired long-QT syndrome. The risk of drug-induced TdP varies during the menstrual cycle, suggesting that dynamic changes in levels of ovarian steroids, estradiol and progesterone, have cyclical effects on cardiac repolarization. Although increasing evidence suggests that the mechanism of this involves effects of female hormones on cardiac repolarization, it has not been completely clarified. In addition to well-characterized transcriptional regulation of cardiac ion channels and their modifiers through nuclear hormone receptors, we recently reported that physiological levels of female hormones modify functions of cardiac ion channels in mammalian hearts. In this review, we introduce our recent findings showing that physiological levels of the two ovarian steroids have opposite effects on cardiac repolarization. These findings may explain the dynamic changes in risk of arrhythmia in women during the menstrual cycle and around delivery, and they provide clues to avoiding potentially lethal arrhythmias associated with QT prolongation.

Follicular development in a 7-day versus 4-day hormone-free interval with an oral contraceptive containing 20 mcg ethinyl estradiol and 1 mg norethindrone acetate

Background Combined oral contraceptive (COC) formulations with 20 mcg ethinyl estradiol (EE) have a greater incidence of ovarian hormone production and follicular development, which can be managed by shortening the number of hormone-free days per COC cycle. This study evaluates differences in follicular development during a 7-day versus 4-day hormone-free interval in a COC regimen with 20 mcg EE and 1 mg norethindrone acetate. Study Design Forty-one healthy women were randomized in an open-label fashion to this formulation in either a 24/4 or a 21/7 day regimen for three cycles. Estradiol, progesterone, follicle-stimulating hormone, luteinizing hormone and inhibin B were measured daily from Cycle 2, Day 21 to Cycle 3, Day 3 and on Day 7 of Cycle 3. Follicular diameter and Hoogland score were calculated on Cycle 2, Days 21, 24 and 28 and Cycle 3, Days 3 and 7. Results Sixty-six percent of subjects in the 21/7 group and 70% of the subjects in the 24/4 group developed a follicle greater than 10 mm diameter. Ovarian steroid hormone levels, Hoogland scores and bleeding patterns were not statistically significant between the groups. Conclusion In contrast to prior studies, this analysis suggests no difference in follicle development or bleeding patterns among women receiving a 21/7 or 24/4 regimen of a 20-mcg EE/1-mg norethindrone acetate COC.

Loss of Cannabinoid Receptor CB1 Induces Preterm Birth

BackgroundPreterm birth accounting approximate 10% of pregnancies in women is a tremendous social, clinical and economic burden. However, its underlying causes remain largely unknown. Emerging evidence suggests that endocannabinoid signaling via cannabinoid receptor CB1 play critical roles in multiple early pregnancy events in both animals and humans. Since our previous studies demonstrated that loss of CB1 defers the normal implantation window in mice, we surmised that CB1 deficiency would influence parturition events.Methods and FindingsExploiting mouse models with targeted deletion of Cnr1, Cnr2 and Ptgs1 encoding CB1, CB2 and cyclooxygenase-1, respectively, we examined consequences of CB1 or CB2 silencing on the onset of parturition. We observed that genetic or pharmacological inactivation of CB1, but not CB2, induced preterm labor in mice. Radioimmunoassay analysis of circulating levels of ovarian steroid hormones revealed that premature birth resulting from CB1 inactivation is correlated with altered progesterone/estrogen ratios prior to parturition. More strikingly, the phenotypic defects of prolonged pregnancy length and parturition failure in mice missing Ptgs1 were corrected by introducing CB1 deficiency into Ptgs1 null mice. In addition, loss of CB1 resulted in aberrant secretions of corticotrophin-releasing hormone and corticosterone during late gestation. The pathophysiological significance of this altered corticotrophin-releasing hormone-driven endocrine activity in the absence of CB1 was evident from our subsequent findings that a selective corticotrophin-releasing hormone antagonist was able to restore the normal parturition timing in Cnr1 deficient mice. In contrast, wild-type females receiving excessive levels of corticosterone induced preterm birth.ConclusionsCB1 deficiency altering normal progesterone and estrogen levels induces preterm birth in mice. This defect is independent of prostaglandins produced by cyclooxygenase-1. Moreover, CB1 inactivation resulted in aberrant corticotrophin-releasing hormone and corticosterone activities prior to parturition, suggesting that CB1 regulates labor by interacting with the corticotrophin-releasing hormone-driven endocrine axis.

Effect of age, gender, menopausal status, and ovarian hormonal level on rTMS in treatment-resistant depression

This study examines how gender and menopausal status contribute to age effect on the antidepressant efficacy of repetitive transcranial stimulation (rTMS). Thirty-one women (17 premenopausal, 14 postmenopausal), and 16 men with treatment-refractory bipolar/major depression underwent 10 consecutive sessions of rTMS. Mood symptoms and female hormones were measured. ANOVA-R revealed a significant gender (p<0.05) and time effect (p<0.001) on the Hamilton Depression Rating Scale (HAM-D) score. Percentage reduction of the rating correlated negatively with age in women (p<0.001). While no difference in the rTMS response was observed between male and premenopausal female patients (68.8% and 70.6%, respectively), postmenopausal women responded least (0%). We also found that greater improvement of depression score was associated with a higher estradiol/progesterone ratio in premenopausal women (p<0.05), suggesting an important role of female hormones in the therapeutic response. Regression analysis revealed that menopausal status and ovarian steroid levels, but not age, were the main determinants of antidepressant efficacy of rTMS in females. This is the first study to specifically investigate the effect of female hormones on rTMS therapeutic effect. Our data support changes in menopausal status and ovarian steroid levels as effectors of mood and the CNS neural substrate response to rTMS in refractory depression. However, the restricted number of patients and the shorter duration of rTMS treatment and follow-up might influence its generalization. Further study examining the interactions between mood, ovarian hormones, and rTMS treatment is warranted.

Silver Lining for Women with Migraines

Several observations suggest links between ovarian steroid levels and migraine headaches: Migraine is two to three times more prevalent in women than in men; most women with migraines report more headaches during menses; and migraine frequency drops during pregnancy, which is associated with sustained elevated estrogen levels. Given that estrogen exposure is associated with breast …

Lower levels of prepulse inhibition of startle response in pregnant women compared to postpartum women

During the postpartum period, estradiol and progesterone levels decline from very high levels during late pregnancy to low levels within 48h of parturition. This period is associated with dysphoric states such as the postpartum blues. Animal studies have suggested an enhanced acoustic startle response and deficient prepulse inhibition (PPI) of startle response following progesterone withdrawal and during the postpartum period. The aim of the current study was to compare acoustic startle response and PPI in healthy third trimester pregnant women and healthy postpartum women. Twenty-eight healthy pregnant and 21 healthy postpartum women (examined between 48h and 1 week after delivery) were recruited for the study. In addition, to evaluate the time-course of postpartum changes 11 early postpartum women (examined within 48h following delivery) were included in the study. The eyeblink component of the acoustic startle reflex was assessed using electromyographic measurements of m. Orbicularis Oculi. Twenty pulse-alone trials (115dB 40ms broad-band white noise) and 40 prepulse-pulse trials were presented. The prepulse stimuli consisted of a 115dB 40ms noise burst preceded at a 100ms interval by 20ms prepulses that were 72, 74, 78 or 86dB. Pregnant women exhibited lower levels of PPI compared to late postpartum women, p<0.05. There was no difference between pregnant women and postpartum women examined within 48h of delivery. There was no difference in startle response or habituation to startle response between pregnant women and either of the two groups of postpartum women. Healthy women display lower levels of PPI during late pregnancy when estradiol and progesterone levels are high compared to the late postpartum period when ovarian steroid levels have declined.

Moderate anxiety, whether acute or chronic, is not associated with ovarian suppression in healthy, well‐nourished, Western women

The relationship between psychological stress and reduced fecundity has been a matter of speculation and investigation for decades. Most previous studies have been compromised, however, by a number of problems including ambiguous direction of causation, poorly operationalized variables, and the confounding of psychological with energetic stress. We present a two-part study of the relationship between moderate anxiety, both acute and chronic, and daily measures of ovarian steroid and corticosteroid levels in saliva. Anxiety, as a particular form of psychosocial stress, was measured by the Spielberger Stait-Trait Anxiety Inventory as well as by a self-reported daily stress score. In the first part, 23 college juniors taking the Medical College Admissions Test (MCAT) were studied the month before and the month after the test, and again several months later, and compared at the same time points with 27 controls. In the second part, chronic anxiety levels were assessed in 95 women between 27 and 41 years of age and analyzed in relation to daily levels of salivary ovarian and corticosteroids over one menstrual cycle. The sample sizes are sufficient to allow for confidence in negative results. No statistically significant differences in ovarian or corticosteroid levels were observed whether between the MCAT and control subjects in part one, between the MCAT subjects before and after the MCAT test in part one, or between high and low anxiety subjects in part two. The results indicate that moderate levels of anxiety, whether acute or chronic, are not associated with suppressed ovarian function in healthy women.

Review of apoptotic and non-apoptotic events in non-ciliated cells of the mammalian oviduct

Reproductive organs are known to undergo dynamic changes during the oestrus cycle and pregnancy. Cell growth and regeneration of the reproductive tissues are closely correlated with ovarian steroid hormone levels. This review focuses on apoptotic and non-apoptotic degenerative events within oviduct epithelium that occur in a species-, cycle-, and segment-specific manner. Epithelial extrusion of larger cell fragments including nuclei and whole cells is the characteristic feature of non-apoptotic cell loss of non-ciliated cells in large (pig, sheep, goat, cattle) and small animals (dog). This mechanism of epithelial cell loss is most frequently observed in the luteal phase of the oestrus cycle and after progesterone treatment, respectively. Using light- and electron-microscopic techniques, typical apoptotic epithelial cells characterized by extensive nuclear and cytoplasmic fragmentation are found very sporadically in most species. In contrast, oviduct epithelial cells of subhuman primates and cats in part show marked signs of apoptosis, which could be explained by their respective cycle-specific characteristics. Recent investigations using histochemical markers of apoptosis and our own findings in the porcine oviduct suggest that the degenerative process in the mammalian oviduct includes the death of numerous epithelial cells by apoptosis. Advancement in the knowledge of elimination of oviduct epithelial cells is necessary to understand the physiological process of epithelial renewal and pathological processes caused by imbalances between cell renewal and elimination.

A comparison of blood spot vs. plasma analysis of gonadotropin and ovarian steroid hormone levels in reproductive-age women

To compare LH, FSH, P, and E(2) levels obtained from blood spot vs. plasma (single-visit study) and to determine whether blood spots can document circulating hormone levels during ovulatory cycles (menstrual-cycle study). Cross-sectional study. Academic center. Women 18-35 years of age with regular menstrual cycles and no recent use of hormonal contraception. Women contributed both a blood spot sample from a finger-stick and a plasma sample through venipuncture on a random day within their menstrual cycle (n = 100, single study visit). Five additional women were followed for an entire menstrual cycle with biweekly venipuncture and daily self-collected blood spot sampling. Samples were analyzed for FSH, LH, P, and E(2). Correlation between blood spot and plasma levels. Significant positive correlations were found between the blood spot and plasma samples in the single-visit study (r(2): FSH, 0.91; LH, 0.93; P, 0.83; and E(2,) 0.70). Two of the 5 menstrual-cycle study women had ovulatory cycles based on P levels (>3 ng/mL) and an LH surge. Daily blood spot sampling was better able to document hormonal changes than biweekly venipuncture. Blood spot monitoring of FSH, LH, P, and, to a lesser extent, E(2), appears to be as valid as traditional plasma assays for clinical research and care.

Anterior Pituitary Gene Expression with Reproductive Aging in the Female Rat1

Although reproductive aging in women is classically attributed to loss of ovarian follicles, recent data have suggested that the entire hypothalamic-pituitary-ovarian axis undergoes functional changes with time. The aim of this study was to characterize age-related changes in pituitary gene expression for factors with known importance for gonadotroph function, including 1) steroid hormone receptors (Esr and Pgr), 2) orphan nuclear receptors [Nr5a1 (steroidogenic factor-1) and Nr5a2 (liver receptor homologue-1)], and 3) pituitary-derived polypeptides (activin, inhibin, and follistatin), as well as 4) gonadotropin subunits and 5) GnRH receptors. We chose to utilize a middle-aged rat model for these studies. Young (Y; 3-mo-old) and middle-aged (MA; 9- to 12-mo-old) rats were ovariectomized, primed with estradiol, and injected with progesterone to induce an LH surge. The mRNA levels for the gonadotropin subunits and GnRH receptors were decreased in middle-aged females relative to young animals. Nr5a1 and follistatin mRNA levels were significantly greater in Y versus MA animals following ovariectomy. Furthermore, steroid-induced regulation of these genes was lost in the MA animals. Regulation of the Nr5a2, Inhba, and Inhbb transcripts was also limited to the young animals. In contrast, there were no significant differences in the mRNA levels of Esr or Pgr family members between age groups at any time point. Although this in vivo model normalizes ovarian steroid levels, it does not control for potential differences in GnRH stimulation with aging. Therefore, in a second set of experiments, we used an in vitro perifusion system to compare the effects of pulsatile GnRH in the two age groups. Nr5a1 mRNA expression was greater in Y than MA animals and was significantly decreased by GnRH pulses in both age groups. Follistatin mRNA levels increased significantly with GnRH treatment in Y animals but were not significantly changed in the MA females. Taken together, these data demonstrate gene-specific blunting of pituitary gene expression postovariectomy and during the steroid-induced surge in middle-aged rats. We propose that age-related changes in pituitary physiology may contribute to reproductive senescence.

Sex and Menstrual Cycle Effects on Progressive Ratio Measures of Cocaine Self-Administration in Cynomolgus Monkeys

Fluctuations in ovarian steroid hormones across the menstrual/estrous cycle influence the abuse-related effects of acute cocaine administration in women and chronic cocaine self-administration in rodents, but there have been no comparable studies in non-human primates. The interactions among sex, menstrual cycle phase, and cocaine self-administration (0.0032, 0.01, and 0.032 mg/kg/injection (inj)) under a progressive ratio schedule were investigated in four female and two male cynomolgus monkeys. Females were given unrestricted access to cocaine across 54 menstrual cycles, and males were studied over 23 pseudo-cycles of 30 days duration. Ovulatory cycles were defined by luteal phase elevations in progesterone and 44 cycles were ovulatory. During ovulatory menstrual cycles, females reached significantly higher progressive ratio break points than males at all three unit doses of cocaine (P<0.001). During anovulatory cycles, females also reached significantly higher break points than males for 0.032 mg/kg/inj cocaine (P<0.01). Progressive ratio break points for cocaine (0.01 and 0.032 mg/kg/inj) did not vary significantly as a function of ovarian steroid hormone levels during the follicular and the luteal phase of ovulatory menstrual cycles, or during anovulatory cycles. Progressive ratio break points for 0.0032 mg/kg/inj cocaine were significantly higher during the follicular phase than during the late luteal phase (P<0.05-0.001). There were no systematic changes in progressive ratio break points in male pseudo-cycles. Significant cocaine dose-related sex differences were observed, but no consistent changes in cocaine self-administration as a function of menstrual cycle phase, or levels of estradiol and progesterone, were detected in female cynomolgus monkeys.

Long-term estrogen deficiency lowers regional blood flow, resting systolic blood pressure, and heart rate in exercising premenopausal women

The cardiovascular consequences of hypoestrogenism in premenopausal women are unclear. Accordingly, the influence of menstrual status and endogenous estrogen (E(2)) exposure on blood pressure (BP), heart rate (HR), and calf blood flow in young (18-35 yr) regularly exercising premenopausal women with exercise-associated menstrual aberrations was investigated. Across consecutive menstrual cycles, daily urinary ovarian steroid levels were analyzed, and the area under the curve was calculated to determine menstrual status and E(2) exposure. BP, HR, blood flow, vascular conductance, and resistance were measured at baseline and following ischemic calf exercise. Exercising subjects consisted of 14 ovulatory (ExOv), 10 short-term (anovulatory and <or=100 days amenorrhea; ST-E(2) Def), and 8 long-term (>100 days amenorrhea; LT-E(2) Def) E(2)-deficient women. Nine sedentary ovulatory subjects (SedOv) were also studied. All groups were similar in age (24.8 +/- 0.7 yr), height (164.8 +/- 1.3 cm), weight (57.9 +/- 0.9 kg), and body mass index (21.3 +/- 0.3 kg/m(2)). E(2)-deficient groups had lower (P < 0.002) E(2) exposure compared with ovulatory groups. Resting systolic BP, HR, blood flow, and vascular conductance were lower (P < 0.05) and vascular resistance higher (P < 0.05) in LT-E(2) Def compared with both ovulatory groups. Peak ischemic blood flow, vascular conductance, and HR were also lower (P < 0.05) and vascular resistance higher (P < 0.05) in LT-E(2) Def compared with all other groups. Our findings show that exercising women with long-term E(2) deficiency have impaired regional blood flow and lower systolic BP and HR compared with exercising and sedentary ovulatory women. These cardiovascular alterations represent markers of altered vascular function and autonomic regulation of which the long-term effects remain unknown.

Protocoles en cas de mauvaise réponse

Primary ovarian insufficiency (POI) is a rare but important cause of ovarian hormone deficiency and infertility in women. In addition to causing infertility, POI is associated with multiple health risks, including bothersome menopausal symptoms, decreased bone density and increased risk of fractures, early progression of cardiovascular disease, psychologic impact that may include depression, anxiety, and decreased perceived psychosocial support, potential early decline in cognition, and dry eye syndrome. Appropriate hormone replacement therapy (HRT) to replace premenopausal levels of ovarian sex steroids is paramount to increasing quality of life for women with POI and ameliorating associated health risks. In this review, we discuss POI and complications associated with this disorder, as well as safe and effective HRT options. To decrease morbidity associated with POI, we recommend using HRT formulations that most closely mimic normal ovarian hormone production and continuing HRT until the normal age of natural menopause, ∼50 years. We address special populations of women with POI, including women with Turner syndrome, women with increased risk of breast or ovarian cancer, women approaching the age of natural menopause, and breastfeeding women.

Oestrogen, Cognition and the Maturing Female Brain

Many women complain of memory and other cognitive difficulties at times that are associated with changes in ovarian steroid levels. However, the biological mechanisms through which ovarian steroids exert these effects remains poorly understood. Furthermore, the effect of hormone therapy, especially oestrogen therapy, on cognition and brain function in healthy women, and its role in the prevention of Alzheimer's disease, remains controversial. Here, we review the evidence that, in healthy women, ovarian steroids/oestrogen affects brain regions crucial to higher cognitive function at the macroscopic, microscopic, functional and neurotransmitter levels.