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Concept: Corpus luteum


Sex hormones fluctuate during the menstrual cycle. Evidence from animal studies suggests similar subtle fluctuations in hippocampal structure, predominantly linked to estrogen. Hippocampal abnormalities have been observed in several neuropsychiatric pathologies with prominent sexual dimorphism. Yet, the potential impact of subtle sex-hormonal fluctuations on human hippocampal structure in health is unclear. We tested the feasibility of longitudinal neuroimaging in conjunction with rigorous menstrual cycle monitoring to evaluate potential changes in hippocampal microstructure associated with physiological sex-hormonal changes. Thirty longitudinal diffusion weighted imaging scans of a single healthy female subject were acquired across two full menstrual cycles. We calculated hippocampal fractional anisotropy (FA), a measure sensitive to changes in microstructural integrity, and investigated potential correlations with estrogen. We observed a significant positive correlation between FA values and estrogen in the hippocampus bilaterally, revealing a peak in FA closely paralleling ovulation. This exploratory, single-subject study demonstrates the feasibility of a longitudinal DWI scanning protocol across the menstrual cycle and is the first to link subtle endogenous hormonal fluctuations to changes in FA in vivo. In light of recent attempts to neurally phenotype single humans, our findings highlight menstrual cycle monitoring in parallel with highly sampled individual neuroimaging data to address fundamental questions about the dynamics of plasticity in the adult brain.

Concepts: Combined oral contraceptive pill, Menopause, Estradiol, Menstrual cycle, Endometrium, Corpus luteum, Progesterone, Ovulation


Concern has been raised over chemical induced disruption of ovarigenesis during fetal life resulting in long-lasting consequences only manifesting themselves much later during adulthood. A growing body of evidence suggest that prenatal exposure to the mild analgesic acetaminophen/paracetamol can cause such a scenario. In this Review, we therefore discuss three recent reports that collectively indicating that prenatal exposure in a window around 13.5 days post coitum in both rats and mouse can result in reduced female reproductive health. The combined data show that the exposure results in reduction in primordial follicles, irregular cycling, premature absence of corpus luteum, as well as reduced fertility, resembling premature ovarian insufficiency syndrome in humans that is linked to premature menopause. This could be problematic in the Western world where the age at childbirth is continuously being delayed and because acetaminophen is recommended during pregnancy for pain, fever. We therefore highlight an urgent need for more studies to verify these data including both experimental and epidemiological approaches.

Concepts: Pregnancy, Reproduction, Fetus, Uterus, Reproductive system, Fertility, Menstrual cycle, Corpus luteum


It is well known that adult humans detect images of snakes as targets more quickly than images of flowers as targets whether the images are in color or gray-scale. When such visual searches were performed by a total of 60 adult premenopausal healthy women in the present study to examine whether their performance would fluctuate across the phases of the menstrual cycle, snake detection was found to become temporarily enhanced during the luteal phase as compared to early or late follicular phases. This is the first demonstration of the existence of within-individual variation of the activity of the fear module, as a predictable change in cognitive strength, which appears likely to be due to the hormonal changes that occur in the menstrual cycle of healthy women.

Concepts: Hormone, Menopause, Estrogen, Menstrual cycle, Endometrium, Corpus luteum, Follicle-stimulating hormone, Luteal phase


The aim of this study was to evaluate the efficiency of presynchronization with GnRH and PGF(2α) or with progesterone on overall Ovsynch (OVS) outcomes in noncyclic dairy cows. Cows were scanned 7d apart with ultrasonography to determine cyclicity. Noncyclic cows (n=281; no corpus luteum on ovaries at both examinations) were randomly divided into 3 groups. In the GP group (n=108), the cows received GnRH and PGF(2α) (PGF) administrations 7d apart, and OVS was started 11d after PGF (GnRH-7 d-PGF-11 d-OVS). In the P4 group (n=90), the cows were treated for 7d with an intravaginal progesterone (P4) implant (PRID), and then OVS was started 11d after removal of the implant (7d PRID-11 d-OVS). The control group (CON, n=83) did not receive any presynchronization, and OVS was started at the same time as in the other groups (18 d-OVS). The percentage of cows that became cyclic at the beginning of OVS was lower in the CON group (38.6%; 32/83) than in the presynchronization groups (66.7%, 72/108 in GP; 71.1%, 64/90 in P4). The response to the first GnRH of OVS did not differ among groups (63.9%, 53/83 in CON; 67.6%, 73/108 in GP; 63.3%; 57/90 in P4), and synchronization rates were similar among the groups (74-82%). The cows that responded to presynchronization treatments (GP or P4) had higher pregnancy per artificial insemination (P/AI) than did nonresponding cows. Pregnancy per AI at 31d did not differ between groups (30.1%, 25/83 in CON; 43.5%, 47/108 in GP; and 35.6%, 32/90 in P4). However, CON cows (24.1%, 20/83) had lower P/AI at 62d than GP cows (41.7%, 45/108). Embryonic loss was higher in CON (20%, 5/25) compared with the P4 group (3%, 1/32). The administration of GnRH followed by PGF or exogenous progesterone (PRID) similarly increased the percentage of cows that became cyclic before Ovsynch in noncyclic cows, but fertility did not improve. However, the cows that responded to presynchronization had higher fertility rates than the nonresponding cows.

Concepts: Pregnancy, Milk, Fertility, Menstrual cycle, Endometrium, Corpus luteum, Ovulation, Artificial insemination


Tonic gonadotrophin secretion throughout the menstrual cycle is regulated by the negative feedback actions of ovarian oestradiol (E(2) ) and progesterone (P). While kisspeptin neurones in the arcuate nucleus (ARC) of the hypothalamus appear to play a major role in mediating these feedback actions of the steroids in non-primate species, this issue has been less well studied in the monkey. Here, we used immunohistochemistry (IHC) and in situ hybridization (ISH) to examine kisspeptin and KISS1 expression, respectively, in the mediobasal hypothalamus (MBH) of adult ovariectomised (OVX) rhesus monkeys. We also examined kisspeptin expression in the MBH of ovarian intact females, and the effect of E(2) , P and E(2) +P replacement on KISS1 expression in OVX animals. Kisspeptin or KISS1 expressing neurons and pronounced kisspeptin fibres were readily identified throughout the ARC of ovariectomised monkeys, but in intact animals on the other hand kisspeptin cell bodies were small in size and number and only fine fibers were observed. Replacement of OVX monkeys with physiologic levels of E(2) , either alone or with luteal phase levels of P, abolished KISS1 expression in the ARC. Interestingly, P replacement alone for 14 days also resulted in a significant downregulation of KISS1 expression. These findings support the view that, in primates, as in rodents and sheep, kisspeptin signaling in ARC neurones appears to play an important role in mediating the negative feedback action of E(2) on gonadotrophin secretion, and indicate a need to further study their regulation by P. © 2013 British Society for Neuroendocrinology.

Concepts: Hypothalamus, Macaque, Menstrual cycle, Primate, Corpus luteum, Rhesus Macaque, Puberty, Monkeys in space


We evaluated the cortisol response of adult female eland (n=8) that were handled in hydraulic chute daily or 3×/week. Females were divided into two groups and each group (n=4) successively received two estrous cycle synchronization treatments: (1) two injections of prostaglandin (PG-PG) F(2)α at 11day intervals and (2) oral administration of altrenogest for 7days and an injection of PGF(2)α on day 7 (Alt-PG). Blood samples were collected 3×/week during the synchronization (Synch) and expected luteal phase (Nonintensive) periods, and daily during the expected time of induced (Intensive 1) or natural (Intensive 2) estrus. Overall, mean cortisol levels were highest during Intensive 1, followed by Intensive 2, Synch and Nonintensive periods. Individual eland were the most significant source of variation for cortisol level. The frequency of handling and the synchronization treatment significantly affected cortisol levels in 3/8 and 4/8 females, respectively. In conclusion, in response to increased frequency of handling, eland cortisol levels rose transiently and returned to baseline within few days after more intensive handling. Thus, the eland females were tolerant to and recovered from the effects of repeated daily handling.

Concepts: Cortisol, Menstrual cycle, Corpus luteum, Bovinae, Antelope, Common Eland, Giant Eland, Taurotragus


Evidence for menstrual cycle-related mood fluctuations in the general population of women has been mixed. While most previous research has relied on retrospective self-report and did not consider possible moderators, the present study aimed to examine cycle-related mood variations in daily life and possible moderating effects of anxiety and trait rumination. We examined 59 women aged 18-44 years with natural menstrual cycles between January and October 2012. Mood components of calmness, positive valence, energetic-arousal, and irritability were assessed using smartphones by ambulatory assessment ten times per day on eight days across the cycle. The menstrual, follicular, ovulatory, and late luteal phases were each covered by two consecutive assessment days. Moderators were assessed with questionnaires. Hierarchical linear models revealed higher calmness in the luteal and menstrual than in the follicular and ovulatory phase, while menstrual cycle did not exhibit significant main effects on other mood components. Anxiety and ruminative self-reflection moderated the association between menstrual cycle and all mood variables. Specifically, highly anxious and ruminative women showed an increase in irritability, while women with lower anxiety and lower rumination were protected against mood deterioration toward the end of the cycle. Further research could examine whether reducing anxiety and rumination helps to prevent PMS-related syndromes.

Concepts: Estrogen, Menstrual cycle, Endometrium, Corpus luteum, Progesterone, Ovulation


Asian small-clawed otters (ASCO) are a popular species to exhibit in zoological institutions globally, and are found in managed populations in the United States, Europe, Asia, and Australia. Captive breeding of these otters is integral to population sustainability, with management programs using pedigree analyses to make specific breeding recommendations to ensure long-term genetic viability. Because of the familial social structure of ASCO and limited space within zoos, physical separation of animals is not always possible for temporary breeding prevention, and short-term contraception may be preferred. In US zoos, Suprelorin (deslorelin; Virbac Australia, Milperra, Australia), a GnRH agonist, has been recommended for contraception of female carnivores, due to its small implant size and lack of side effects often associated with hormone-based contraceptives. However, the duration of reproductive suppression with Suprelorin may be excessive and reversibility (i.e. resumption of cyclicity, ovulation, and pregnancies) in implanted females across a range of species has been variable, unpredictable, and prolonged. Since 2006, 49 female ASCO have been implanted with Suprelorin at least once, and, of these, only two females have shown confirmed reversibility with pregnancies. No ASCO females implanted more than once have thus far exhibited reversibility (personal communication, AZA Wildlife Contraceptive Center, St. Louis, MO, USA). In this case study, fecal hormone monitoring of one female ASCO implanted with Suprelorin three times (Dec 2007, Jan 2009, Mar 2010), showed a lack of ovarian cyclicity and ovulation during the three years since her last implant. In an attempt to induce ovarian follicular growth and ovulation, this female was injected (IM) with exogenous gonadotropins (100IU of equine chorionic gonadotropin followed 80h later with 3000IU of porcine luteinizing hormone). Fecal progesterone monitoring confirmed ovulation followed by a 76 day pseudopregnancy, with temporal characteristics similar to those previously reported in naturally cycling ASCO (Bateman et al. 2009 Zoo Biol. 28, 107-126). Following the induced pseudopregnancy and ~55 days of basal progestin levels, this female was observed breeding with a cohabitating ASCO male. Fecal hormone monitoring revealed subsequent ovulation and the occurrence of another pseudopregnancy of normal duration. These preliminary findings suggest that exogenous gonadotropin treatment may be useful for promoting resumption of normal ovarian cyclicity and ovulatory responses in ASCO following prolonged reproductive suppression with Suprelorin.

Concepts: Pregnancy, Luteinizing hormone, Menstrual cycle, Corpus luteum, Human chorionic gonadotropin, Ovulation, Aonyx, Oriental Small-clawed Otter


The mammary gland undergoes development and regression over the course of the ovarian cycle under the regulation of ovarian hormones. Macrophages are implicated as local mediators of this tissue remodelling and may also affect immune surveillance and tumour incidence. To investigate cycle-related changes in macrophage phenotype, mammary gland cells from naturally cycling Cfms-Gfp mice recovered at estrus, metestrus, diestrus and proestrus were analysed by flow cytometry. Macrophage expression of MHCII was highest in the proestrus phase, with a 1.6-fold increase compared to the metestrus phase. Similarly, macrophage expression of CD204 was 1.9-fold higher at proestrus compared to estrus. Conversely, macrophage expression of NKG2D was increased at metestrus and diestrus by 7-fold and 5-fold respectively compared to estrus. To investigate hormonal regulation of macrophage phenotype, an ovariectomy and hormone replacement model was utilised. Ovariectomized mice were stimulated with exogenous estradiol and progesterone to induce early alveolar development, then given progesterone receptor antagonist RU486 to elicit alveolar bud regression. Progesterone and estradiol in combination reduced macrophage expression of MHCII and CD204 by 5-fold and 3-fold respectively, and increased macrophage expression of NKG2D by 4-fold. Administration of RU486, following estradiol and progesterone, reversed the macrophage phenotype. These results reveal an essential requirement for ovarian hormones in regulating macrophage phenotype in the mammary gland, and indicate that progesterone is particularly critical for controlling macrophage antigen presentation and immune surveillance capacity.

Concepts: Immune system, Hormone, Estrogen, Receptor, Menstrual cycle, Endometrium, Corpus luteum, Progesterone


Macrophages are prominent in the uterus and ovary at conception. Here we utilize the Cd11b-Dtr mouse model of acute macrophage depletion to define the essential role of macrophages in early pregnancy. Macrophage depletion after conception caused embryo implantation arrest associated with diminished plasma progesterone and poor uterine receptivity. Implantation failure was alleviated by administration of bone marrow-derived CD11b+F4/80+ monocytes/macrophages. In the ovaries of macrophage-depleted mice, corpora lutea were profoundly abnormal, with elevated Ptgs2, Hif1a, and other inflammation and apoptosis genes and with diminished expression of steroidogenesis genes Star, Cyp11a1, and Hsd3b1. Infertility was rescued by exogenous progesterone, which confirmed that uterine refractoriness was fully attributable to the underlying luteal defect. In normally developing corpora lutea, macrophages were intimately juxtaposed with endothelial cells and expressed the proangiogenic marker TIE2. After macrophage depletion, substantial disruption of the luteal microvascular network occurred and was associated with altered ovarian expression of genes that encode vascular endothelial growth factors. These data indicate a critical role for macrophages in supporting the extensive vascular network required for corpus luteum integrity and production of progesterone essential for establishing pregnancy. Our findings raise the prospect that disruption of macrophage-endothelial cell interactions underpinning corpus luteum development contributes to infertility in women in whom luteal insufficiency is implicated.

Concepts: Pregnancy, Estrogen, Menstrual cycle, Endometrium, Corpus luteum, Human chorionic gonadotropin, Implantation, Ovary