13.63: Menstrual Cycle - Biology

13.63: Menstrual Cycle - Biology

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What's the most important part of the female menstrual cycle?

A menstrual cycle calendar. A lot of things to keep track of. And for a few very important reasons, it is important to know when a woman is ovulating. But what's the most important part of the female menstrual cycle? That depends on who you ask.

Menstrual Cycle

Ovulation, the release of an egg from an ovary, is part of the menstrual cycle, which typically occurs each month in a sexually mature female unless she is pregnant. Another part of the cycle is the monthly period, or menstruation. Menstruation is the process in which theendometrium of the uterus is shed from the body. The menstrual cycle is controlled by hormones from the hypothalamus, pituitary gland, and ovaries.

Phases of the Menstrual Cycle

As shown in Figure below, the menstrual cycle occurs in several phases. The cycle begins with menstruation. During menstruation, arteries that supply the endometrium of the uterus constrict. As a result, the endometrium breaks down and detaches from the uterus. It passes out of the body through the vagina over a period of several days.

Phases of the Menstrual Cycle. The menstrual cycle occurs in the phases shown here.

After menstruation, the endometrium begins to build up again. At the same time, a follicle starts maturing in an ovary. Ovulation occurs around day 14 of the cycle. After it occurs, the endometrium continues to build up in preparation for a fertilized egg. What happens next depends on whether the egg is fertilized.

If the egg is fertilized, the endometrium will be maintained and help nourish the egg. The ruptured follicle, now called the corpus luteum, will secrete the hormone progesterone. This hormone keeps the endometrium from breaking down. If the egg is not fertilized, the corpus luteum will break down and disappear. Without progesterone, the endometrium will also break down and be shed. A new menstrual cycle thus begins.


For most women, menstrual cycles continue until their mid- or late- forties. Then women go through menopause, a period during which their menstrual cycles slow down and eventually stop, generally by their early fifties. After menopause, women can no longer reproduce naturally because their ovaries no longer produce eggs.


  • The menstrual cycle includes events that take place in the ovary, such as ovulation.
  • The menstrual cycle also includes changes in the uterus, including menstruation.
  • Menopause occurs when menstruation stops occurring, usually in middle adulthood.


  1. Define menstruation.
  2. What is menopause? When does it occur?
  3. What is the corpus luteum?
  4. Compare and contrast what happens in the menstrual cycle when the egg is fertilized with what happens when the egg is not fertilized.
  5. Make a cycle diagram to represent the main events of the menstrual cycle in both the ovaries and the uterus, including the days when they occur.

Moon Cycle & The Menstrual Cycle

One last post on this Full Moon evening. In honor of the start of my cycle today, here is an article on the Moon cycle, related to our Menstrual cycle & our emotions.

Have you ever paid attention to the moon cycle, and the magical relationship it has with your menstrual cycle? The moon cycle has 29.5 days, changing from the waxing new moon of increasing light, to the full moon of total illumination, to the dark waning moon of decreasing light, and back to the waxing new moon of increasing light again.
Month after month, the moon cycle mirrors a woman’s menstrual cycle, which coincidently has an average length of 29.5 days as well. And similar to the moon cycle, a woman’s menstrual cycle changes from the menstruation of new growth, to the ovulation of full power and blossom, to the pre-menstrual phase of harvest and degeneration, and back to menstruation of renewal again.
All life forms have cycles of birth, growth, death, and renewal that are mirrored in the progressive phases of the moon cycle. I think a better understanding of the moon cycle and its rhythms and energetic influences can help us better appreciate the rhythmic dance of our own menstrual cycles, to be in harmony with it rather than to be at odd with it.
So how’s your menstrual cycle in relation to the moon cycle? Do you menstruate on the new moon or on the full moon? What’s the moon phase when you ovulate?
I read that the natural cycle of women who live and sleep out in the open away from artificial light is to ovulate on the full moon and menstruate on the new moon. But this is not the case for most modern women whose natural rhythms are largely affected by artificial light.
Some women may menstruate on the crescent moon, some on the full moon, some on the waning moon, and others on the new moon. According to Dragontime by Luisa Francia, specific moon phase energies, when magnified by menstruation can be freed up and made available for use if we choose to work with them.

Waxing moon represents new beginnings and growth. New ideas are being planted. New processes are coming into play. New experiences and events are within reach.
The energy of the waxing moon menstruation is inwards and self-nourishing. It’s time to think, to learn, to read, and to plan. During this time, you might be open to important learning, to receive knowledge, to set intentions, and to make new plans.
The goddess associated with the waxing moon is Persephone, a virgin goddess who walked the path to the underworld and was initiated into womanly bleeding. She’s the guardian of the crescent moon menstruation.

The full moon represents fire, abundance, power and vitality. It’s time to claim one’s own power, make decisions, work changes, and bring something into being.
The energy of full moon menstruation is outward, world-nourishing. Feasts and celebration go well with full moon bleeding. The transformational quality of the fire energy makes it an ideal time to learn to transform negative energies into positive ones: rage into creative action, belly cramps into sensuousness.
Ishtar, the Red Goddess of Babylon is the guardian of this menstrual fire.

The waning moon represents maturity and harvest. It’s time for persistence, for making reality out of the visions and impulses.
The energy of waning moon bleeding is outward, world nourishing. It’s time to tend the blooms of the full moon energy, and to make your vision a reality. It takes persistence, patience, and hard work. But the harvest is within reach if you do.
The goddess of this time, Demeter, a mother goddess is responsible for the cycles of life on earth, letting the fruits and grains ripen for harvest, in preparation for the next cycle when she’ll withdraw to tend to her own nourishment, letting the earth become barren while she mourns for her daughter.

The new moon represents the dark and mysterious power of the deep. Existing structures have fulfilled their purposes, and need to be destructed, or reconstructed to make room for the new.
The energy of new moon bleeding is inwards, self-nourishing. During this time, anxieties, memories, and experiences may rise up, eager to be dealt with. It’s a good time to take stock, and to draw conclusions from them. New moon menstruation is a strong time of healing and renewal.
The goddess of this time is Hecate, the woman at the joining of three roads, the guardian of mysteries and knowledge, the reaper, the dark one, the crone.
What’s the moon phase of your menstruation? Does this information resonate with you? As far as I know, it’s not backed up by scientific studies, but rather, myths and traditions that have been passed on from generations to generations. My philosophy is to take what’s useful for you, and leave the rest.
I hope it’ll help you gain a better understanding of your own menstrual cycle and its rhythms, and develop a more harmonious relationship with it.

Matrix Metalloproteinases (MMPs)

The MMP family of enzymes contributes to both normal and pathological tissue remodeling. MMPs play a key role in the migration of normal and malignant cells through the body. They also act as regulatory molecules, both by functioning in enzyme cascades and by processing matrix proteins, cytokines, growth factors and adhesion molecules to generate fragments with enhanced or reduced biological effects.

Domain Structure & Function

Figure 1. MMPs can facilitate tumor cell metastasis and angiogenesis. Adapted from Opdenakker, G. & J. Van Damme (1992) Cytokine 4:251.

The matrix metalloproteinases (MMPs) are members of a family of at least 15 Zn-dependent endopeptidases that function extracellularly (Table 1). 1 The MMPs each contain a protease domain that has a conserved HExGHxxGxxHS/T sequence in which the three Histidine residues form a complex with a catalytic Zn atom. In addition, all MMPs contain a regulatory domain (pro-piece) with a conserved PRCGxPD motif that is responsible for maintaining latency in MMPs via binding of the cysteine residue to the active site Zn. The simplest MMP is MMP-7 (matrilysin), which consists of a pro-piece and catalytic domain only. The other MMPs maintain this basic unit but have a variable number of structural domains added. Although most MMPs are secreted proteins, the recently described membrane-type MMPs (MT-MMPs) are anchored to the cell membrane by a transmembrane and intracytoplasmic domain. X-ray crystallography has shown that the catalytic domains of the different MMPs have similar structure, but the topology of the active site clefts differs, accounting for some of the differences in substrate specificities. Differences in the other domains confers further substrate specificity, regulates binding to matrix proteins, and determines interactions with the Tissue Inhibitors of Metalloproteinases (TIMPs), the natural inhibitors of MMP activity. 2

Substrates & Nomenclature

Much of the early literature suggested that each MMP had its own particular substrate. 1 This concept led to the use of substrate-focused nomenclature for MMPs such that the collagenases broke down intact fibrillar collagens, gelatinases degraded denatured collagen, and metalloelastase attacked elastin. It is now recognized that MMPs usually degrade multiple substrates, with considerable substrate overlap between individual MMPs. For example, interstitial collagenase (MMP-1) is capable of degrading casein, gelatin, a-1 antitrypsin, myelin basic protein, L-Selectin, pro-TNF and IL-1 beta and pro-MMP-2 and -9. 72-kDa gelatinase (MMP-2) can degrade fibrillar collagen, elastin, IGF-binding proteins, FGF receptor and can activate MMP-1, -9 and -13. MMP-12 is highly active against type IV collagen, gelatin, fibronectin, vitronectin and plasminogen, but it is not very effective at degrading elastin. See Table 1 for a list of substrates that can be cleaved by purified MMPs in vitro.

In an attempt to break the link between name and function, all MMPs are now given an MMP number, such that Interstitial collagenase is MMP-1, etc. (Table 1). There are holes in this system. There is no MMP-4, -5 or -6, as the activities could not be ascribed to a specific gene product, and MMP-18 is known only as a Xenopus enzyme. As with all other enzymes, MMPs have an EC classification, although this lags well behind the MMP designation.

  • Collagenase
  • Fibroblast Collagenase
  • Interstitial Collagenase
  • 72 kDa Gelatinase
  • Gelatinase A
  • Type IV Collagenase
  • Neutrophil Gelatinase
  • Stromelysin-1
  • Transin
  • Matrilysin
  • PUMP
  • Neutrophil Collagenase
  • Collagenase I
  • 92 kDa Gelatinase
  • Gelatinase B
  • Stromelysin-2
  • Stromelysin-3
  • Macrophage Metalloelastase
  • Collagenase-3
  • MT-MMP-1
  • MT-MMP-2
  • MT-MMP-3
  • MT-MMP-4
  • Enamelysin

Role in Physiology and Pathology

Although the link between single MMPs and individual substrates is not as direct as once thought, it is clear that as a family, the MMPs are capable of breaking down any extracellular matrix component (see Table 1). In normal physiology, MMPs produced by connective tissue are thought to contribute to tissue remodeling in development, in the menstrual cycle, and as part of repair processes following tissue damage. The obvious destructive capability of MMPs initially focused most research onto diseases that involve breakdown of the connective tissues (e.g., rheumatoid arthritis, cancer and periodontal disease). Leukocytes, particularly macrophages, are major sources of MMP production. MMPs released by leukocytes play vital roles in allowing leukocytes to extravasate and penetrate tissues, a key event in inflammatory disease. Opdenakker proposed that MMP action not only permits leukocyte emigration into tissues and causes tissue damage, it also generates immunogenic fragments of normal proteins that may escalate autoimmune disease. In an analogous way, metastatic cancer cells also use MMPs to get in and out of tissues and to establish a blood supply (Figure 1). 4 Drug companies have synthesized low molecular weight MMP inhibitors that have shown efficacy in models of these diseases, reinforcing their central role in pathology. 5

The MMP axis is highly regulated to avoid excessive tissue damage. Most MMPs, with the exception of 72 kDa gelatinase and the MT-MMPs, are not constitutively expressed in normal tissues. Inflammatory cytokines such as IL-1 and TNF, growth factors such as TGF-beta and noxious stimuli are required to initiate transcription. MMPs are also expressed as inactive zymogens (the pro-piece must be dissociated from the catalytic domain before the enzyme is activated). This dissociation can be achieved by autocatalysis or by the action of enzymes such as furin, plasmin or even other MMPs. For example, the activation of pro-MMP-2 occurs at the surface of many cells and is mediated by MT-MMPs. Once activated, MMPs are subject to inactivation by TIMPs and by binding to plasma proteins such as alpha-2 macroglobulin. It is thought that the local balance of MMP expression and activation versus the level of TIMP governs the level of destruction mediated by MMPs. This is of great significance when studying MMP involvement in disease processes.

In order to implicate a particular MMP in a disease, several overlapping approaches have been taken. Each has its advantages and disadvantages (Table 2). Development of a comprehensive picture of MMP involvement in any tissue culture system or in vivo disease model likely would require several of these methods.

  • MMP specific
  • Can measure changes in mRNA for multiple MMPs in small samples
  • High throughput
  • Primers easy to design and test
  • Does not measure protein or activity
  • Can be MMP specific
  • Can localize MMP expression
  • Antibodies can cross react with other MMPs
  • Does not discriminate active and inactive enzyme
  • Labor intensive
  • Low sensitivity
  • MMP specific
  • High throughput of samples
  • MMPs found in blood and tissue fluids
  • High sensitivity possible
  • May crossreact with other MMPs
  • May detect inactive or inhibitor -complexed MMPs
  • Can detect active MMP
  • Can be very sensitive
  • May not be specific for particular MMP
  • Subject to sample interference
  • MMP specific
  • Costly
  • Requires establishment of disease model in knock out strain
  • Knock out may be compensated for in development
  • Direct relevance to therapy
  • MMP specific inhibitors have not yet been described

The MMP/Cytokine Connection

Figure 2. The MMP/Cytokine Connection

The MMP axis has several areas of overlap with the cytokine network. As described above, inflammatory cytokines or growth factors can regulate the expression of MMPs. Cytokine activation of cells can also lead to increased processing of MMPs from the inactive zymogens to the active enzymes. Cytokines and their receptors can also be substrates for MMP action (Figure 2). Pro-inflammatory cytokine IL-1 beta can be cleaved and inactivated by MMP-1, -2, -3, and -9. 9 In addition, the degradation of matrix proteins such as decorin can liberate growth factors such as TGF-beta that are sequestered on the matrix. 10 Many membrane-bound cytokines, receptors and adhesion molecules can be released from the cell surface by the action of metalloproteinases, referred to as sheddases or convertases. 11, 12 This may down regulate cell surface signaling by removal of a receptor or extend the sphere of influence of a molecule by release of a soluble active form. The consequences of this will depend on the molecule. For example, soluble TNF cleaved from the cell surface is pro-inflammatory, whereas TNF receptors cleaved from a cell act as soluble TNF inhibitors. In contrast, the cleaved soluble IL-6 receptor acts to stabilize IL-6 and the complex acts as an IL-6 agonist.

Although classical MMPs can process many of these cell surface molecules, members of the reprolysin or adamalysin clan of metalloenzymes may contribute much of the sheddase or convertase activity at the cell membrane. These enzymes have a catalytic site similar to that of the MMPs, but they have a different domain structure. The best characterized enzyme is the TNF-alpha converting enzyme (TACE or ADAM-17). 13-14 This enzyme was initially isolated from cell membranes using a TNF substrate assay to follow purification. Combined inhibitors of MMP and sheddase activity have been produced. They are active in models of inflammatory diseases, such as multiple sclerosis, where a cytokine drive has been implicated. 15

Pathophysiological Changes in Female Rats with Estrous Cycle Disorder Induced by Long-Term Heat Stress

High-temperature exposure is detrimental to women’s reproductive health however, the impact caused by long-term high temperature is not comprehensive, and a stable model of estrous cycle disorder induced by a high temperature is yet lacking. Herein, we aimed to establish a stable and effective model of estrous cycle disorder in female rats induced by long-term heat stress to study its physiological and pathological characteristics and explore the underlying mechanism. In the present study, female Sprague-Dawley rats with normal estrous cycles were exposed to the temperature of

(2 h/d, 1 time/d) hot cabin at more than 90 days. Consequently, after long-term heat stress, no difference was detected in body weight and rectal temperature, but the estrus cycle was prolonged, the uterine organ index was increased, pathological changes occurred, the increase latitude of stress hormones heat shock protein 70 (Hsp70) and corticosterone (CORT) decreased, estradiol (E2) and luteinizing hormone (LH) levels decreased, follicle stimulating hormone (FSH) and prolactin (Prl) levels increased, gonadotropin-releasing hormone (GnRH) and thyroid hormone (T4) showed no difference, and insulin (INS) decreased significantly. Moreover, the mRNA expression of the sex hormone receptor in the uterus and ovary was altered. Therefore, the estrous cycle disorder in female rats can be induced by regular heat stress for 90 days, which can be considered the pioneer method. Subsequently, prominent physiological and pathological characteristics and disruption in the hypothalamic-pituitary-gonadal (HPG) axis were noted.

1. Introduction

High-temperature stress affects the menstrual function of career women, such as soldiers, textile workers, and steel workers, resulting in a significant increase in the incidence of abnormal menstruation. Although the effects of short-term heat exposure on female reproductive function have been studied [1], the mechanism of the impact has not been elucidated. With the increase in global temperature, the expansion of high-temperature environment and the prolonged duration of high-temperature are obvious. Also, the changes in the reproductive function of professional women in a long-term high-temperature environment need to be clarified.

Interestingly, significant gender differences are noted in the coping mechanisms of stressors [2]. Progesterone and estrogen have a direct effect on the response to stress, which varied at different stages of the estrous cycle [3]. Hitherto, only a few studies have focused on the changes in reproductive function induced by long-term heat stress. Also, the short-term heat exposure affected the estrous cycle was focused [4]. However, the disorder during the long-term exposure to high temperature was not apparent, and the physiological and pathological responses need to be elucidated. Therefore, establishing a stable and effective model of estrous cycle disorder caused by long-term heat stress is imperative to clarify the effects and mechanisms of the reproductive system in working women. Thus, the current study established the estrous cycle disorder model and studied the pathophysiological characteristics of female rats in the long-term hyperthermic environment.

The disorder of estrous cycle is often accompanied by the change of hormone levels, and the functions of hormones are accomplished by binding to hormone receptors in the ovary and uterus. Therefore, the changes in the levels of sex hormones and their receptors are important in detecting contents of estrous cycle disorder. The change of the hormone receptor mRNA level is a quantitative response to the gene function and can auxiliary support the change in sex hormone concentration. RT-qPCR has also been widely used to assess the mRNA expression level because of its advantages, such as accuracy and sensitivity [5, 6]. So, we tested the hormone receptors’ mRNA expression via RT-qPCR and detected the hormone protein levels by ELISA. In addition, combined with other pathophysiologic changes and quantitated the conditions of the model, to observe the physiological and pathological responses to high temperature on the reproductive health of female animals.

2. Materials and Methods

2.1. Animals

Specific pathogen-free female Sprague-Dawley (SD) rats, weighing

, were obtained from Weitong Lihua Experimental Animal Technology Co., Ltd. (Beijing, China) and housed at and RH 45–60% humidity under 12 h light-dark cycle with free access to food and water. The animals were fed into the cages for two days, and then vaginal cytological smears were performed at the same time every morning and evening. A total of 44 rats with regular estrous cycles were randomly divided into two groups: (1) control group, fed under the condition of standard temperature and humidity, and (2) heat stress group, each rat was exposed to heat from a small animal heat chamber ( , RH for 2 h/day (9 : 00 to 11 : 00) for at least 90 days with food and water ad libitum. Blood samples from the medial canthus of 10 rats in two groups were collected at day 0, day 1, and day 90 after heat exposure. Within 24 h after the last heat exposure, blood samples of 10 rats were withdrawn from the abdominal aorta during interestrus in each group. Sera were obtained by centrifugation of the blood at 3000 rpm for 10 min and stored at -80°C subsequently, these rats were euthanized. The uterus and ovaries of female rats were excised and stored in liquid nitrogen until further use.

All procedures relating to animal care and use were implemented in strict accordance with the National Institutes of Health Guide for the Care and Use of Laboratory animals (NIH Publications No. 8023, revised 1978) and were approved by the Ethics Review Committee of the Institute of Environmental and Operational Medicine.

2.2. Body Weight and Rectal Temperature Test

The body weight and rectal temperature of the animals were measured before and after 2 h heat exposure every 10 days. Digital balance (Jiangsu, Tong Jun) and thermal probe (1529 thermometer, Fluke Corporation) were used to detect the body weight and rectal temperature, respectively [7].

2.3. Estrous Cycle Assessment

The estrous cycle was determined according to the morphological changes in the vaginal exfoliated cells. In the experimental stage, vaginal lavage was performed daily from 8 : 00 to 9 : 00 and 20 : 00 to 21 : 00. The hematoxylin-eosin (H&E) staining was observed under a light microscope at ×10 and ×40 to detect the cellular changes. According to the proportion of the three cell types, the estrus cycle was determined. The estrous period was divided into proestrus (I), estrus (II), anaphase (III), and interestrus (IV) [8].

2.4. Organ Index of Uterus and Ovary Test

After the rats were sacrificed, the uterus and ovaries of the rats were excised and weighed, and the organ index was calculated according to the ultimate body weight of the rats.

2.5. H&E Staining

The uterus and ovary were fixed in 4% formaldehyde for 72 h, followed by H&E staining. The histopathological changes were observed under a microscope (Nikon digital sight DS-FI2, Japan).

2.6. Enzyme-Linked Immunosorbent Assay (ELISA) Test

The levels of serum estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), progesterone (P), prolactin (Prl), testosterone (T), Insulin (INS), thyroxine (T4), gonadotropin-releasing hormone (GnRH), heat shock protein 70 (Hsp70), and corticosterone (CORT) were measured using a commercial ELISA kit (USCN-LIFE™, China), according to the manufacturer’s instructions.

2.7. qPCR Analysis

Total RNA was extracted from the uterus and ovary in rats in both groups by RNA extraction kit (TakaRa, Japan). RT-qPCR was used to detect the expression levels of estrogen receptor (ER), follicle-stimulating hormone receptor (FSHR), luteinizing hormone receptor (LHR), progesterone receptor (PR), prolactin receptor (PrlR), and testosterone receptor (TR) genes. β-Actin was used as the internal reference gene. The primers used for the detection of ER, FSHR, LHR, PR, PrlR, TR, and β-actin are described in Table 1. The expression of the target gene mRNA was analyzed by 2 -ΔΔCt method.

2.8. Statistics

All the experimental data were expressed as

error of the mean (SEM). Statistical analyses were performed using SPSS22.0. The independent sample

- test as well as one-way ANOVA was used to analyze the differences between two groups and among multiple groups, respectively.

and/or indicated statistical significance.

3. Results

3.1. Estrous Cycle Disorder Model in Female Animals Induced by High Temperature

The body weight of rats in both groups continued to increase during the experiment. The body weight of the heat exposure group was unaltered from day 10 to day 20, and the weight gain was similar to that of the control group after day 30 (Figure 1(a)). The rectal temperature in the heat exposure group showed a rising trend, followed by a decline, which was significantly higher than that in the control group from day 1 to day 30 ( ), and no difference was observed after day 30 (Figure 1(b)). The rate of cumulative disorder in the estrous cycle in the heat exposure group was significantly higher than that of the control rats (heat exposure group: 68.18% control group: 13.63% ) (Figures 1(c) and 1(d)). During the continuous heat exposure, the number of cycles in the heat exposure group was

, which was significantly lower than that in the control group (

, ) (Figure 1(e)). The normal estrous cycle lasted for 4-5 days and was extended by continuous exposure to the thermal environment (heat exposure group:

days control group: 4.27 ± 0.21days (Figure 1(f)). The Hsp70 results showed that there was no difference between the control group and day 0 of the heat stress group it was significantly higher on day 1 and day 90 than day 0 of the heat stress group ( and , respectively) (Figure 1(g)). The level of serum CORT also was significantly higher on day 1 and day 90 than on day 0 of the heat stress group ( ) and the control group ( ). Although it was still higher on the day 90, it was significantly lower than on day 1 ( ) (Figure 1(h)).

). The body weight of the rats was measured every 10 days. (b) Effects of heat exposure on

( ). The of the two groups of rats was determined in the rectum at 5 cm by an animal rectal thermometer every 10 days. (c) Microphotographs ( ) of cellular characteristics for the identification of the estrus stage. Proestrus smear mainly consisted of nucleated epithelial cells (I) an estrus smear primarily consisted of anucleated cornified cells (II) a metestrus smear consisted of the same proportion among leukocytes anucleated cornified cells, and nucleated epithelial cells (III) and a diestrus smear primarily consisted of leukocytes (IV). (d) Effects of heat exposure on cumulative estrous cycle disorder rate ( ). (e) Effects of heat exposure on periodic numbers ( ). (f) Effects of heat exposure on estrus cycle duration ( ). (g) The content of serum Hsp70 in the heat stress group ( ). (h) The content of serum CORT in the heat stress group ( ). The protein concentration of serum Hsp70 and CORT was detected by ELISA. The blood samples from the medial canthus of two groups’ rats were collected at day 0, day 1, and day 90. Values were presented as

and vs. the control group, # and ## vs. the heat stress group (day 0), and and △△ vs. the heat stress group (day 90).

3.2. Long-Term Heat Stress Affected the Organ Index and Histopathological Changes in Reproductive Organs in Female Rats

The results showed that the uterine index in the heat exposure group was significantly higher than that in the control group ( ), and the uterine epithelial height was similar (Figure 2(c)). However, no significant difference was detected in the ovarian index between both groups (Figure 2(a)). Also, the morphology of the ovary in the heat-exposed group did not differ from that of the control group (Figures 2(b) and 2(i), II). The uterine structure of female rats in the control group was intact (Figure 2(b), III, V, VII, and IX) also, the high columnar epithelium, fibrous cell stroma, and glands were intact and bright without any abnormality. In the heat exposure group, the uterine cavity of the female rats was narrow, and the luminal epithelial cells of the endometrium (Figure 2(b), VII, black arrow) showed an irregular morphology with epithelial cytoplasmic vacuolization (Figure 2(b), IV, black arrow) and local cell proliferation. In addition, the dilation of the uterine glands (Figure 2(b), X, yellow arrow) and a small number of neutrophils were detected in the lamina propria (Figure 2(b), VI, yellow arrow).

. (c) Graphical representation of uterine epithelial height ( ). Values are presented as the mean

. vs. the control group.

3.3. Long-Term Stress Affected Sex Hormones and Stress Hormones Levels in Female Rats

The results showed that the levels of serum E2 and LH in the heat exposure group were significantly lower than those in the heat exposure group ( ), while those of FSH and Prl increased significantly ( ). No significant difference was detected in T and P between the two groups (

) (Figure 3(a)). The level of serum INS in the heat exposure group was significantly increased as compared to that in the control group however, no difference was detected in the levels of T4 and GnRH (Figure 3(b)).

3.4. Gene Expression of Sex Hormone Receptors in the Uterus and Ovary of Female Rats by Long-Term Heat Stress

The expression of sex hormone receptors, including TR, ER, FSHR, LHR, PR, and PrlR in the uterus and ovary, was detected by RT-qPCR. The data showed that the level of ER-α, PR, and PrlR in the womb of female rats in the heat exposure group was significantly higher than that in the control group ( ) (Figure 4(a)). In addition, the ovarian sex hormone genes, including ER-α, LHR, and PR were significantly decreased, while FSHR and PrlR were significantly increased in the heat exposure group as compared to the control group ( and , respectively) (Figure 4(b)).

4. Discussion

The impact of temperature on the fertility function in women, especially in working women, has attracted attention due to the complexity of the reproductive system of women.

However, a unified female rat model of estrous cycle disorder caused by long-term heat exposure similar to occupational exposure is yet lacking the characteristics of estrous cycle disorder are not found to be consistent, and the related mechanism is not yet clarified. At present, most of the studies on heat stress and heat injury models focus on economic animals such as buffalo [9], dairy cow [10], pig [11], and ewe [12]. It is not suitable for the further study of the human menstrual cycle. There are few studies on heat stress in female rats, and the modeling conditions are different, and the conclusions are inconsistent [1, 4, 13, 14]. Herein, we proposed a 90-day heat stress model to redefine the temperature, duration, and frequency of heat exposure and established a stable and effective rat estrus cycle disorder model on the premise of no heatstroke. The estrous cycle is a periodic change in the nonpregnant reproductive activity of female placental mammals. The disorder in a physiological period indicates that the reproductive function of women could be damaged. Therefore, we regard estrous cycle disorder as an essential marker of changes in reproductive function in female rats induced by long-term heat stress. Previous studies have shown that short-term heat stress does not change the estrous cycle, and the disorder of the estrous cycle induced by long-term heat stress was only reported by a Russian group in 1975 [15]. In the study, female rats ( ) were exposed to 40°C for 12 months. The average duration of the estrous period was significantly prolonged.

Simultaneously, no significant changes were detected in the body weight and core temperature ( ) of the two groups before and after heat stress. Only in the initial 30 days of the experiment, the weight gain was decreased significantly and the was increased remarkably in the heat stress group rats. Thus, body weight was a key index to reflect the nutritional status and energy metabolism of the body. The sudden decline in weight gain during acute heat exposure within 1–30 days might be related to decreased appetite and reduced food intake and energy metabolism [16], while another possibility is that heat exposure leads to increased intestinal permeability [17, 18]. Reports [19] have shown that layer chickens had a 20% reduced feed intake during hot and humid weather. The intestinal epithelial barrier in rats was damaged in acute heat exposure for 25 min (45°C, relative humidity 55%), resulting in a significant decrease in the expression of occludin, claudin, ZO-1, and JAM-A, and a significant decrease in the number of Paneth and goblet cells from to [20]. Paneth and goblet cells are important components of intestinal epithelium, and the depletion of these cells will lead to epithelial barrier defect [21]. is often used to indicate the efficiency of the body thermoregulation system. Previous studies reported [22, 23] that during the heat exposure period, the rose rapidly and linearly, while of animals was less than the environmental heat load ( ). The thermoregulatory center dysfunction occurred when reached . Typically, rat is defined as a thermal injury (heat stock) marker [22, 23]. In the current study [7, 24], the temperature was limited to , >36.0°C, and< 41.0°C, which is “compensable heat stress” [25]. The was invariable between 38.0 and 39.5°C, without any obvious abnormal behavior or death in the heat stress group rats. In this study, the levels of sex hormones were disrupted in the estrous cycle disorder of female rats. The wet weight of the uterus increased, and the organ index in the experimental group was significantly higher than that in the control group. The uterine function of the female rats in the heat stress group was damaged. Previous studies reported that the organ index has a narrow range, and the increase indicates that the organ may exhibit hyperemia, edema, or hypertrophy [26]. Furthermore, under high-temperature exposure for 12 weeks, the spleen and liver of the rats atrophied and then returned to normal. The possible reason was that a series of complex immunomodulatory responses occurred after stress stimulation. On the other hand, the long-term immune response induced immune tolerance of the organs, leading to the hypertrophy of the organs [27]. Some other studies showed that estrogen causes a rapid increase in the microvascular permeability in the rodent uterus, resulting in a significant increase in stromal edema and uterine wet weight [28]. The current results showed that serum E2 was downregulated, and ER mRNA was upregulated in the uterus. Herein, we speculated that the growth of damp uterine pressure and partial edema might be induced by the proliferation of uterine glands, as well as the increase in the E2-triggered uterine microvascular permeability.

Hsp70, as a classic stress marker, is a kind of protein responds to long-term or chronic stress and can slow down the magnification response of stress-related, and it has a certain protective effect on the body. Corticosterone in rodents indicates the state of chronic stress [29]. In our study, the serum Hsp70 and corticosterone levels of female rats increased significantly after the first day of high temperature exposure and showed a downward trend after continuous heat exposure for 90 days, which may help with the rats’ adaptation over time.

was found in the heat exposure group, indicating ovarian hyporesponsiveness or ovarian insufficiency [30]. In women, the synergistic effect of LH and FSH on ovarian follicles and granulosa cells led to an increase of estradiol in the blood, which is essential for the production of estrogen and progesterone [31]. Thus, FSH/LH is one of the clinical indexes to evaluate the ovarian reserve function. In a normal physiological state, the body can maintain FSH/LH in the normal range through self-regulation. However, under stress, the function of the hypothalamic-pituitary-gonadal (HPG) axis is affected, especially the intervention of GnRH. This disrupts the feedback regulation of the hypothalamus-pituitary-ovary (HPO) axis, which in turn, might cause a decline in the ovarian reserve function. The current results about serum LH, FSH, P, LHR, FSHR, and PR mRNA suggested that long-term heat stress leads to the dysfunction of HPO and the damage of ovarian function. Furthermore, the content of serum GnRH in the heat exposure group did not show any significant change, which could be attributed to the different stages of stress. Thus, it is suggested that the balance of the HPO axis has not been established and may be involved in the formation of estrus cycle disorders.

In hyperthermia stress, circulating blood Prl, a stress hormone, is considered to be related to the central nervous system. Its concentration reflects the activity of neurotransmitters [32] and is highly correlated to the core body temperature [33]. After 90 days of chronic heat stress, the content of serum Prl in the experimental group increased, and the expression of PrlR mRNA in the uterus and ovary was upregulated this phenomenon was consistent with the stress state of the rats in this group.

Insulin [34] and thyroxine [35] are vital hormones on the HPO axis and essential aspects of endocrine changes under heat stress. However, the majority of the studies suggested that the concentration of insulin was increased [36], while our study (Figure 3(b)) presented the opposite result [37]. This discrepancy might be related to the degree of thermal adaption of the body following heat exposure. High temperature led to a decrease in food intake, affecting the energy balance [38]. Moreover, the low level of LH in the blood inhibited the secretion of INS, thus reducing the glucose metabolism of the body to resist the heat effect of high temperature because LH was closely related to INS. Also, we observed that the serum thyroid T4 concentration decreased in the heat stress group, albeit without a significant difference. Reportedly, the thyroid secretory function is decreased during heat stress, the primary metabolism is weakened, and the production of body heat is reduced to maintain the balance of heat production and heat dissipation [39]. Under acute heat stress, T4 secretion decreased [39, 40] however, after long-term mild heat stress, the body showed thermal adaptation, and the T4 level gradually returned to the average level.

In summary, we investigated the physiological and pathological characteristics of estrus cycle disorder caused by long-term high temperature in female rats. The conditions for the model were definite, the physiological and pathological responses were obvious, and the HPG axis was disrupted. The present study would provide the experimental basis for the study of the regulatory mechanism of the estrus cycle disorder for an in-depth understanding of this field.


RH:Relative humidity
FSH:Follicle-stimulating hormone
LH:Luteinizing hormone
GnRH:Gonadotropin releasing hormone

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

Conflicts of Interest

The authors declare no conflicts of interest.

Authors’ Contributions

Gaihong An and Xuewei Chen are co-first authors. GHA, WJ, and XWC designed and supervised the study. GHA and JJC completed the experiments. GHA, CL, and LZ analyzed and interpreted the data. MFW drew the figures, and GHA wrote the manuscript. XWJ helped to write the paper. WJ, DFY, and QM edited the manuscript. All authors read and approved the final version.


This study was supported by the grants of Tianjin Institute of Environmental and Operational Medicine (BWS17J025). We thank Yujie Cui and Hao Chu very much for scientific support.


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22 - Gender Differences in the Outcome of Acute Myocardial Infarction

Despite women's inherent protection towards coronary heart disease (CHD), once women develop an acute myocardial infarction (AMI) they appear to loose much of their protection compared with men. In spite of smaller infarcts and less severe coronary narrowing, women hospitalized for AMI have more severe presentation, higher rates of complications, and higher mortality compared with men. These gender-related outcome differences are much more marked in younger than in older patients. In part, these differences are attributable to the higher prevalence of preexisting diseases and risk factors in women compared with men. However, in many studies the gender-related outcome differences remain unexplained. Possible additional reasons for the poorer outcome of women after AMI relative to men include delayed symptom recognition, diagnosis and referral of women with CHD a potential undertreatment of women with AMI psychosocial factors differences in AMI pathophysiology between women and men and a higher prehospital mortality among men. All these potential mechanisms are discussed.


Claus Yding Andersen is professor in human reproductive physiology at University of Copenhagen and has headed the Laboratory of Reproductive Biology at the University Hospital of Copenhagen, Denmark since 2009. He received his MSc and DMSc from the University of Copenhagen. He was a member of the team that introduced IVF to Denmark in the mid-1980s and has worked with reproduction since then. He is leading a national programme for cryopreservation of human ovarian tissue. Other major research interests include ovarian endocrinology and human embryonic stem cells. He has published more 250 peer-reviewed papers and has given many international presentations.

Prolactin receptor

Prolactin receptors are present in the mammillary glands, ovaries, pituitary glands, heart, lung, thymus, spleen, liver, pancreas, kidney, adrenal gland, uterus, skeletal muscle, skin and areas of the central nervous system. [42] When prolactin binds to the receptor, it causes it to dimerize with another prolactin receptor. This results in the activation of Janus kinase 2, a tyrosine kinase that initiates the JAK-STAT pathway. Activation also results in the activation of mitogen-activated protein kinases and Src kinase. [42]

Human prolactin receptors are insensitive to mouse prolactin. [43]

On Female Body Experience: “Throwing Like a Girl” and Other Essays

These essays describe diverse aspects of women’s lived body experience in modern Western societies. They combine theoretical description of experience with normative evaluation of the unjust constraints on freedom and opportunity that continue to burden many women. The lead essay rethinks the purpose of the category of “gender” for feminist theory, after important debates have questioned its usefulness. Other essays include reflection on the meaning of being at home and the need for privacy in old age residencies. Aspects of the experience of women and girls that have received little attention . More

These essays describe diverse aspects of women’s lived body experience in modern Western societies. They combine theoretical description of experience with normative evaluation of the unjust constraints on freedom and opportunity that continue to burden many women. The lead essay rethinks the purpose of the category of “gender” for feminist theory, after important debates have questioned its usefulness. Other essays include reflection on the meaning of being at home and the need for privacy in old age residencies. Aspects of the experience of women and girls that have received little attention even in feminist theory are analyzed, such as the sexuality of breasts, or menstruation as punctuation in a woman’s life story. The phenomenology of moving in a pregnant body and the tactile pleasures of clothing are also considered.

Sexual Skin Color Contains Information About the Timing of the Fertile Phase in Free-ranging Macaca mulatta

Females of several primate species undergo cyclical changes of their sexual skin, i.e., the development of a swelling or a change in color. The relationship between intracycle probability of fertility and the size of sexual swellings is well established, but in the only study to combine an objective measure of color with endocrinological data, researchers found no evidence that swelling color contains such information. To evaluate the role of female skin color in the context of sexual signaling further, we investigated whether changes in sexual skin color contain information about the timing of the fertile phase in rhesus macaques (Macaca mulatta), a species in which adult females do not develop sexual swellings, but do express visually detectable changes in the skin color of the face and hindquarters. Using an objective and quantitative measure of color, along with detailed data on fecal progestogen and estrogen metabolite levels collected from 8 females of the Cayo Santiago colony, we show that the ratio of red to green (R/G) for facial and hindquarter skin significantly varies throughout the ovarian cycle. In addition, facial skin R/G is significantly higher during the 5-d fertile phase versus the 5-d periods immediately before or after this time, but no such pattern occurs in hindquarter R/G. This suggests that skin color change in female rhesus macaques may potentially signal information about the intracycle probability of fertility to male receivers, but that only facial skin color may signal reliable information about its timing.

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US Foods Holding Corp. [USFD] Revenue clocked in at $22.84 billion, up 13.63% YTD: What’s Next?

US Foods Holding Corp. [NYSE: USFD] loss -2.77% on the last trading session, reaching $37.85 price per share at the time. The company report on May 24, 2021 that Eighteen US Foods Drivers Inducted Into the International Foodservice Distributors Association Truck Driver Hall of Fame.

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The national program shines a spotlight on the industry’s top drivers for their outstanding service and safety records.

US Foods Holding Corp. (NYSE: USFD) announced that 18 US Foods drivers were named to the 2021 class of the International Foodservice Distributors Association (IFDA) Truck Driver Hall of Fame. The IFDA Truck Driver Hall of Fame honors the exceptional careers and contributions of hard-working professional drivers.

US Foods Holding Corp. represents 221.00 million in outstanding shares, while the company has a total market value of $8.19 billion with the latest information. USFD stock price has been found in the range of $37.45 to $38.60.

If compared to the average trading volume of 2.08M shares, USFD reached a trading volume of 2734186 in the most recent trading day, which is why market watchdogs consider the stock to be active.

Here is what top equities market gurus are saying about US Foods Holding Corp. [USFD]:

Based on careful and fact-backed analyses by Wall Street experts, the current consensus on the target price for USFD shares is $45.24 per share. Analysis on target price and performance of stocks is usually carefully studied by market experts, and the current Wall Street consensus on USFD stock is a recommendation set at 2.00. This rating represents a strong Buy recommendation, on the scale from 1 to 5, where 5 would mean strong sell, 4 represents Sell, 3 is Hold, and 2 indicates Buy.

Piper Sandler have made an estimate for US Foods Holding Corp. shares, keeping their opinion on the stock as Overweight, with their previous recommendation back on April 09, 2021. The new note on the price target was released on January 25, 2021, representing the official price target for US Foods Holding Corp. stock. Previously, the target price had yet another raise from $22 to $45, while BMO Capital Markets kept a Outperform rating on USFD stock.

The Average True Range (ATR) for US Foods Holding Corp. is set at 1.21, with the Price to Sales ratio for USFD stock in the period of the last 12 months amounting to 0.36. The Price to Book ratio for the last quarter was 2.39, with the Price to Cash per share for the same quarter was set at 4.22. Price to Free Cash Flow for USFD in the course of the last twelve months was 16.54 with Quick ratio for the last quarter at 1.00.

Trading performance analysis for USFD stock

US Foods Holding Corp. [USFD] fell into the red zone at the end of the last week, falling into a negative trend and dropping by -1.41. With this latest performance, USFD shares dropped by -5.30% in over the last four-week period, additionally plugging by 15.33% over the last 6 months – not to mention a rise of 77.45% in the past year of trading.

Overbought and oversold stocks can be easily traced with the Relative Strength Index (RSI), where an RSI result of over 70 would be overbought, and any rate below 30 would indicate oversold conditions. An RSI rate of 50 would represent a neutral market momentum. The current RSI for USFD stock in for the last two-week period is set at 44.92, with the RSI for the last a single of trading hit 42.73, and the three-weeks RSI is set at 46.68 for US Foods Holding Corp. [USFD]. The present Moving Average for the last 50 days of trading for this stock 38.81, while it was recorded at 38.72 for the last single week of trading, and 32.41 for the last 200 days.

US Foods Holding Corp. [USFD]: A deeper dive into fundamental analysis

Operating Margin for any stock indicates how profitable investing would be, and US Foods Holding Corp. [USFD] shares currently have an operating margin of +0.45 and a Gross Margin at +16.47. US Foods Holding Corp.’s Net Margin is presently recorded at -0.99.

Return on Total Capital for USFD is now 1.09, given the latest momentum, and Return on Invested Capital for the company is -2.46. Return on Equity for this stock declined to -5.83, with Return on Assets sitting at -1.91. When it comes to the capital structure of this company, US Foods Holding Corp. [USFD] has a Total Debt to Total Equity ratio set at 152.90. Additionally, USFD Total Debt to Total Capital is recorded at 60.46, with Total Debt to Total Assets ending up at 49.83. Long-Term Debt to Equity for the company is recorded at 166.57, with the Long-Term Debt to Total Capital now at 57.42.

Reflecting on the efficiency of the workforce at the company, US Foods Holding Corp. [USFD] managed to generate an average of -$8,692 per employee. Receivables Turnover for the company is 15.95 with a Total Asset Turnover recorded at a value of 1.93.US Foods Holding Corp.’s liquidity data is similarly interesting compelling, with a Quick Ratio of 1.00 and a Current Ratio set at 1.60.

US Foods Holding Corp. [USFD]: An earnings per share (EPS) analysis

With the latest financial reports released by the company, US Foods Holding Corp. posted -0.25/share EPS, while the average EPS was predicted by analysts to be reported at -0.35/share. When compared, the two values demonstrate that the company surpassed the estimates by a Surprise Factor of 28.60%. The progress of the company may be observed through the prism of EPS growth rate, while Wall Street analysts are focusing on predicting the 5-year EPS growth rate for USFD.

An analysis of insider ownership at US Foods Holding Corp. [USFD]

There are presently around $7,933 million, or 96.20% of USFD stock, in the hands of institutional investors. The top three institutional holders of USFD stocks are: VANGUARD GROUP INC with ownership of 18,210,205, which is approximately 1.717% of the company’s market cap and around 0.80% of the total institutional ownership INVESCO LTD., holding 16,970,282 shares of the stock with an approximate value of $642.33 million in USFD stocks shares and FMR LLC, currently with $613.3 million in USFD stock with ownership of nearly -22.2% of the company’s market capitalization.

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Positions in US Foods Holding Corp. stocks held by institutional investors increased at the end of May and at the time of the May reporting period, where 160 institutional holders increased their position in US Foods Holding Corp. [NYSE:USFD] by around 36,822,396 shares. Additionally, 157 investors decreased positions by around 34,181,516 shares, while 48 investors held positions by with 138,599,025 shares. The mentioned changes placed institutional holdings at 209,602,937 shares, according to the latest SEC report filing. USFD stock had 48 new institutional investments in for a total of 13,686,605 shares, while 54 institutional investors sold positions of 4,454,527 shares during the same period.


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    yes, but that's not all ... I hope there will be more

  4. Roweson

    It doesn't come close to me. Who else can say what?

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