Estrogens have been isolated from testes of stallion, bulls, boars, dogs and men. Estrogens may play a role in the pathogenesis of prostatic hyperplasia common in aged dogs, and estrogens receptors are present in prostatic urethra and prostatic glands of dogs. Estrogens like androgens, are transferred from testicular vein to the testicular artery.
In several species, levels of estrogens in the blood of testicular artery are consistently higher than the levels in systemic blood. The mechanisms involved in the transfer of estrogens from vein to artery in the pampiniform plexus and its physiology role are not clear.
Estrogens may be playing important role in regulating the pituitary-gonadal axis. In several species, estrogens inhibit Leydig cell secretion of testosterone Pineda, as it will be mentioned. Sex steroids: Source, Target tissues and Physiological Functions. Modified from Hu et al. Progesterone is produced in the ovaries, the adrenal glands suprarenal , and, during pregnancy, in the placenta. Progesterone is also stored in adipose fat tissue. Progesterone is synthesized by the ovarian corpus luteum, but during pregnancy the main source of P4 is the placenta as in woman,mare and ewe; in cow, the time of placenta takeover is months of pregnancy.
In other species goat, sow, queen, bitch,rabbit, alpaca,camel, llama there is no placenta P4 production at all, the ovarian CL is in charge of the entire P4 for gestation. In mammals, P4, like all other steroid hormones, is synthesized from pregnenolone, which in turn is derived from cholesterol. Androstenedione can be converted to testosterone, estrone and estradiol Figure 1 Wikipedia.
Important functions of P4 are 1 inhibition of sexual behavior; 2 maintenance of pregnancy by inhibiting uterine contractions and promoting glandular development in the endometrium; and 3 promotion of alveolar development of the mammary gland. The synergistic actions of estrogens and progestins are notable in preparing the uterus for pregnancy and the mammary gland for lactation Table 1. In at least one plant, Juglans regia , progesterone has been detected.
In addition, progesterone-like steroids are found in Dioscorea mexicana. It contains a steroid called diosgenin that is taken from the plant and is converted into progesterone. Diosgenin and progesterone are found in other Dioscorea species as well. The switch from the principal steroid product of the maturing follicle estrogens to that of the developing and mature corpus luteum P4 is one of the amazing hallmarks of the ovary sex steroids production occurring during luteinization as described later.
Ovarian granulosa cells and testicular Leydig cells are responsive primarily to LH and synthesize androgens. Ovarian thecal cells and testicular Sertoli cells as well as Leydig cells respond to FSH with conversion of androgens into estrogens Paromatase activity. FSH also stimulates Sertoli cells to synthesize inhibin, activin, and other local bioregulatory factors Norris, Anatomically in the female hypothalamus, there are two GnRH neurons centers.
The first, the surge center, consists of three nuclei called the preoptic nucleus, the anterior hypothalamic area and the suprachiasmatic nucleus. This center releases basal levels of GnRH until it receives the appropriate positive stimulus. This stimulus is known to be a threshold level of estrogen in the absence of P4.
When the estrogen concentration in the blood reaches a certain level, a large quantity of GnRH is released from the terminals of neurons, the cells bodies of which are located in the surge center. In natural condition, the preovulatory surge of GnRH occurs only once during the estrous or menstrual cycle.
The second, the tonic center, releases small episodes of GnRH in a pulsatile fashion similar to a driping faucet. This episodic release is continuous and throughout reproductive life and during the entire estrous cycle Senger, The female in various species have two important periods that mark the reproductive cycle: follicular and luteal phases.
The follicular phase begins after luteolysis that causes the decline in P4. The follicular phase is dominated by E2 produced by ovarian follicles and ends at ovulation. In women, the follicular phase is divided into menses and proliferative period 5 and 9 days respectively ; luteal phase is the secretory phase 14 days.
In domestic animals, the follicular phase is divided in pro-estrus 2 days and estrus 1 day , and the luteal phase in metestrus 4 days and diestrus 14 days. When recruited follicles develop dominance, they produce E2 and inhibin that suppresses FSH secretion from the anterior lobe of the pituitary. Thus, E2 in low concentrations causes a negative feedback suppression on the preovulatory center.
That is, low estrogen reduces the level of firing GnRH neurons in the preovulatory-surge center. However, when E2 levels are high estrus , as they would be during the mid-to late follicular phase figure 2 , the preovulatory center responds dramatically by releasing large quantities of GnRH. This stimulation in response to rising concentrations of E2 is referred to as positive feedback.
During the middle part of the cycle, when E2 levels are low and P4 is high metestrus, diestrus , there is negative feedback on the preovulatory center, thus preventing high amplitude pulses of GnRH. Interesting, when comparing human vs. As reviewed by Murphy, luteinization is a remarkable event involving cell proliferation, cell differentiation, and tissue remodeling that is unparalleled in the adult mammal.
It comprises two major processes: a the terminated proliferation plus rapid hypertrophy and differentiation of the steroidogenic cells of follicle into the luteal cells of the CL. Luteinization is both a qualitative and quantitative change because the mammalian CL produces up to fold greater amounts of steroid P4 than the follicle.
Luteolysis results in cessation of P4 production, in structural regression to forma corpus albicans and into a follicular development and entrance into a new follicular phase. Female cyclicity and gonadal steroids. Each cycle consists of a follicular and a luteal phase. The follicular phase is dominated by the hormone E2 from ovarian follicles. E2 causes marked changes in the female tract for pregnancy. Anestrus stands for periods of time when estrous cycles cease.
Pregnancy, season of the year, lactation, forms of stress and pathology cause anestrus. Amenorrhea refers to the lack of menstrual periods and is caused by many of the same factors that cause anestrus. A menstrual cycle consists of the physiological events that occur between successive menstrual periods about 28 days. No endometrial sloughing menstruations occurs in animal with estrous cycles.
Lutealphase is dominated by P4 from corpus luteum. As the main steroid produced during luteal phase is the P4 it is important to mention about the manipulation of the estrous and menstrual cycles by exogenous administration of P4. Exogenous P4 suppresses estrus and ovulation. When this exogenous P4 is removed or withdrawn, the animal will enter pro-estrus and estrus within 2 to 3 days after removal.
This application is intended to increase the convenience of artificial insemination programs and to facilitate fertility in domestic husbandry animal improving pregnancy rates. In contrast, the use of exogenous P4 in humans oral, transdermal,injectable, implants is intended to block ovulation and minimize pregnancy probability contraception Senger, Upon stimulation by LH, the Leydig cells of the testes produce androgens.
Dihydrotestosterone is found in high enough concentration in peripheral tissue to be of functional importance. Functions of T, as states before, include 1 development of secondary sex characteristics; 2 maintenance of the male duct system; 3 expression of male sexual behavior libido ; 4 function of the accessory glands; 5 function of the tunica dartos muscle in the scrotum; and 6 spermatocytogenesis. The role of T in regulating the release of hypothalamic and gonadotropic hormones is similar to that described for P4 in the female.
Thus, reciprocal action of T with the hypothalamic and gonadotropic hormones is necessary for regulation of normal reproduction in the male Figure 3 Gyeongsang National University. Luteinizing hormone acts on the Leydig cells within the testes. These cells are analogous to the cells of the theca interna of antral follicles in the ovary.
They contain membrane bound receptors for LH. The production of T takes place by the same intracellular mechanism as in the female. The Leydig cells synthesize and secrete T less than 30 minutes after the onset of an LH episode Figure 3. This T secretion is short and pulsatile, lasting for a period of 20 to 60 minutes. It is believed that pulsatile discharge of LH is important for two reasons. First, high concentration of T within the seminiferous tubule is essential for spermatogenesis Senger, Second, Leydig cells become unresponsive to sustained high levels of LH believed to be caused by reduction in the number of LH receptor.
In fact, continual high concentrations of LH result in reduced secretion of T. Intratesticular levels of T are times higher than that of systemic blood. However, testicular T is diluted over times when it reaches the peripheral blood Senger, The role of the pulsatile nature of T is not fully understood.
It is believed that chronically high systemic concentrations of T suppress FSH secretion. Sertoli cells function is FSH dependent. Thus, their function is compromised when FSH is reduced. The periodic reduction in T allows the negative feedback on FSH to be removed.
Sertoli cells also produce inhibin that, as in the female, suppresses FSH secretion from the anterior lobe of the pituitary. The physiologically important hormone that exerts tonic negative feedback upon FSH secretion in men is inhibin B Illingworth et al. Inhibin and androgen binding protein are produced by Sertoli cells under the influence of FSH.
As in the female, inhibin selectively inhibits the release of FSH while not affecting the release of LH. Androgen binding protein binds T, making it available for its functions in spermatozoa production. The stallion and the boar secrete large amount of E2 but since they are secreted as molecules with low physiologic activity they seem to be of little consecuence.
Sertoli cells convert T to E2 utilizing a mechanism identical to the granulosal cell of the antral follicle in the female Senger, The exact role of E2 in male reproduction it is not clear. Spermatogenesis and steroids.
Modified from Senger, There is a pulsatile discharge of LH. Leydig cells produce important concentrations of testosterone T. High concentration of T within the seminiferous tubule, essential for spermatogenesis. Sertoli cells aromatize T from Leydig cell into E2.
Because most steroid receptors in target cells are located in the cytoplasm, they need to get into the nucleus to alter gene expression. This process typically takes at least 30 to 60 minutes. In contrast, other regulatory actions of steroid hormones are manifested within seconds to a few minutes. These time periods are far too rapid to be due to changes at the genomic level and are therefore termed nongenomic or rapid actions, to distinguish them from the classical steroid hormone action of regulation of gene expression.
In some cases, these rapid actions of steroids are mediated through the classical steroid receptor that can also function as a ligand-activated transcription factor, whereas in other instances the evidence suggests that these rapid actions do not involve the classical steroid receptors.
One candidate target for the nonclassical receptor-mediated effects are G protein-coupled receptors GPCRs , which activate several signal transduction pathways. One characteristic of responses that are not mediated by the classical steroid receptors is insensitivity to steroid antagonists, which has contributed to the notion that a new class of steroid receptors may be responsible for part of the rapid action of steroids.
Evidence suggests that the classical steroid receptors can be localized at the plasma membrane, where they may trigger a chain of reactions previously attributed only to growth factors. Identification of interaction domains on the classical steroid receptors involved in the rapid effects, and separation of this function from the genomic action of these receptors, should pave the way to a better understanding of the rapid action of steroid hormones Cato et al.
The biological activity of androgens is thought to occur predominantly through binding to intracellular androgen-receptors, a member of the nuclear receptor family, that interact with specific nucleotide sequences to alter gene expression. This genomic-androgen effect typically takes at least half an hour. In contrast, the rapid or non-genomic actions of androgens are manifested within in seconds to few minutes.
This rapid effect of androgens are manifold, ranging from activation of G-protein coupled membrane androgen receptors or sex hormone-binding globulin receptors, stimulation of different protein kinases, to direct modulation of voltage- and ligand gated ion-channels and transporters. The physiological relevance of these non-genomic androgen actions has not yet been determined in detail.
However, it may contribute to modulate several second messenger systems or transcription factors, which suggests a cross-talk between the fast non-genomic and the slow genomic pathway of androgens Michels and Hoppe, Figure 4. The rapid actions of androgens are mediated by direct binding to the target protein e. The non-genomic androgen action based on receptor level can be mediated by at least three androgen-binding proteins, the classical intracellular androgen receptor, the transmembrane androgen receptor and the transmembrane sex hormone-binding globulin receptor.
For both transmembrane receptors, the non-genomic effect is converted via a G-protein coupled process, whereas binding to intracellular androgen receptors may lead to an activation of several cytosolic pathways. Although some studies implicated benefits of the non-genomic androgen actions on the cardiovascular and neuropsychiatric systems, more detailed research and clinical studies are still required Michels and Hoppe, Increasing evidence suggests that nongenomic effects of testosterone and anabolic androgenic steroids AAS operate concertedly with genomic effects.
Classically, these responses have been viewed as separate and independent processes, primarily because nongenomic responses are faster and appear to be mediated by membrane androgen receptors, whereas long-term genomic effects are mediated through cytosolic androgen receptors regulating transcriptional activity. Actions and pathways of androgens. Modified from Michels and Hoppe, In Chariditi et al. The first well known molecular mechanism is the classic ligand dependent pathways.
Estrogen receptors are kept inactive in the nucleus and cytoplasm of the cell forming a complex with various heat shock proteins hsp that act as chaperones when the cell is not exposed to estrogens. Such proteins are hsp90, hsp70 and hsp56 and by forming a complex with the ERs they are believed to prevent them from binding to their response elements EREs, but also keep them capable of binding to their ligands estrogens with high affinity. When the estrogens diffuse across the cell and nuclear membrane they interact with the inactive form of the ERs and separate them from the hsp-complex.
ERs are now activated and can form homodimers and to a lesser extent heterodimers to bind to their estrogens EREs. The EREs are commonly located in the promoter regions of estrogen target genes and make it possible for the ERs to specifically bind to the DNA and regulate transcription either as enhancers or repressors. Once the complex of the activated ERs together with co-activator proteins such as ligand-dependent activation function-1 and 2: AF-1 and AF-2 is bound to the ERE it can either up- or down-regulate the expression of the target gene.
The second molecular mechanism is the ligand independent. It is possible that the ERs get activated even in the absence of their ligands with the aid of intracellular second messengers. This ligand-independent ER activation is still dependent on AF Another intracellular path that can lead to ER activation in the absence of ligands is via cAMP, a second messenger for G-protein coupled receptors and activates the PKA pathway.
The third signaling pathway is the ERE independent one. Estrogens exert their actions through the two ERs but also through other transcription factors. In this case the ligand-activated ERs do not bind to their EREs but anchor instead to other transcription factors directly bound to DNA in their specific response elements. Thus this, pathway is also referred to as transcription factor cross-talk Figure 5.
Furthermore, the two ERs differ in their capacity to interact with different transcription factors. For example in the presence of 17beta-estradiol, ERa induces AP-1 driven gene transcription, while ERb has an inhibitory effect. This contrasting transcriptional activity is another example of the opposing actions of each ER. The last mechanism is the non-genomic plasma-membrane pathway. The above mentioned mechanisms include the relatively long processes of gene transcription and mRNA translation and are thus insufficient to explain the short-term effects of estrogens that are found.
Intracellular pathways that increase intracellular calcium, cAMP, or the phosphorylation of the cAMP response element binding protein CREB , can result in an instantaneous response of the cell. This pathway does not require transcription of genes via the ERs and is referred to as non-genomic mechanisms of estrogen action, similar to the non-genomic pathways of androgens Charitidi et al. In adults, the interaction of estrogen genomic and nongenomic mechanisms may act to maintain physiology or signal transduction pathways as hormone levels fluctuate across the estrus cycle.
Treatments designed to increase ER activity around the time of menopause, such as cyclic estrogen replacement, may be more beneficial than chronic hormone replacement Foster, Recently, it was published a review about the overlapping nongenomic and genomic actions of thyroid hormone and estrogens and androgens.
Authors concentrate on the tumor cell model, where, for example, estrogens and thyroid hormone have similar MAPK-dependent proliferative actions and where dihydrotestosterone also can stimulate proliferation. Steroids and thyroid hormone have similar anti-apoptotic effects in certain tumors; they also have overlapping or interacting nongenomic and genomic actions in heart and brain cells. Their possible clinical consequences seem of crutial importance for the potential endocrine therapy targeting steroids receptors directly or indirectly hormone or protein with overlapping effects as reported for breast cancer and the nuclear and citoplasmic estrogen receptor and aromatase Davis et al.
Estradiol epigenetic effects have been reported with results providing evidence for mitotic regulation in follicle development by estrogen and demonstrate a previously undiscovered mechanism for induction of cell proliferation in ovarian and mammary gland cells. This epigenetic mark is induced by both FSH and 17beta-estradiol E2 , acting independently. E2-induced H3 phosphorylation fails to occur in mice with inactivated alpha-isoform of the nuclear estrogen receptor.
E2 induction of histone phosphorylation is attenuated by cell cycle inhibition. Further, E2 induces the activity of the mitotic kinase, Aurora B, in a mammary tumor cell model where mitosis is estrogen receptor-alpha dependent Ruiz-Cortes et al. Actions and pathways of estrogens. Modified from Charitidi et al. Four molecular mechanisms of E2 signaling in target cells. The first is the classic ligand dependent pathways. Estrogen receptors ER are liberated from heat shock proteins complex hsp and can continue their nuclear-DNA effect.
The second is the ligand independent. The third is the ERE independent. In this case the ligand-activated ERs do not bind to their EREs but anchor instead to other transcription factors. The fourth is the non-genomic plasma-membrane pathway and does not require transcription of genes via the ERs.
Besides those well documented genomic and non- genomic molecular pathways, it is important to mention the epigenetic regulation. Sex steroids regulation of the initiation of puberty was reported since in murine studies. Immature female rats presented evidence of oestrogen secretion by day 32 of life and an increased sensitivity of the pituitary to LHRH by day These data suggested that in addition to the increased release of GnRH during puberty, a sex steroid induced alteration in the pituitary's responsiveness to GnRH may also be a significant contributory factor in the increase in secretion of gonadotropins at puberty.
The stimulatory effect appeared to be related both to the quantity of sex steroid and the challenging dose of GnRH. These studies show that in addition to changes in sensitivity at the level of the hypothalamus, the CNS and gonads steroid and GnRH modulation of the response of the pituitary gland, are important events in the onset of puberty Mahesh and Nazian, Puberty is associated with an increasing production of androgenic steroids.
Adrenal androgen formation adrenarche , may precede gonadal testosterone synthesis. Both adrenal and gonadal androgens exert their biological effects via the androgen receptor, a nuclear transcription factor modulating a specific transcription regulation of largely unknown genes. During puberty, virilizing actions such as genital enlargement and sexual hair growth can be distinguished from anabolic action such as the gain in muscle strength and general changes in body composition.
Furthermore, androgens play a major role in the initiation and maintenance of spermatogenesis. Thus, different androgenic steroids play an important role in the process of puberty Hiort, Table 2. Male infants have a surge in T levels during the first few months of life.
These levels fall to quite low but greater than in female infants and children until the pubertal rise. Nighttime elevations in serum T concentration are detectable even before the onset of the external signs of pubertal development following the sleep-entrained rises in serum LH.
The daytime levels rise later as the testis volume increases. Testosterone is a substrate for 5-a reductase conversion to dihydrotestosterone and for aromatase conversion to estradiol. The effects on muscle are likely in part due directly to T and indirectly to E2 because of the marked increase in growth hormone-GH and IGF-I levels due to an action of E2 on the hypothalamus and pituitary Rogol, It is about many factors that may be controlling this important physiological process of acquiring reproductive and productive competence.
The exact mechanisms that enable E2 to control GnRH secretion by the hypothalamus during the peripubertal period are still unknown even if since this effect was porposed as mentioned at the beginning of this apart. Other factor that need better understanding is the effect of ferhormones as social clue , including steroids hormones, on the control of puberty onset; olfactory and vomeronasal organs are implicated but the exact pathways is not well defined.
Since female must maintain a successful pregnancy, deliver live offspring and lactate, there a clearly physiological limit to hastened puberty in females Senger, The use of exogenous sex steroids for those purposes male and female is possible but also very questioned because of the secondary effects and the potential food residues meat and milk for human.
Interestingly, Nelson proposed three potential predictors i. Ages of pubertal onset and of declining fertility are hypothesized to be positively correlated with longevity. Concentrations of androgens and estrogens are proposed to be inversely and positively correlated, respectively, with life span Nelson, Thirty years ago research results about the effect of follicular steroids on the maturation and fertilization of mammalian oocytes was reported. Pronuclear development was used to measure the effects on ovine oocytes of altering follicular steroidogenesis during maturation in vitro.
Follicular steroid secretion was altered using enzyme inhibitors and exogenous steroid supplementation. Abnormalities induced during maturation were measured 24 h after transfer of oocytes to the oviducts of inseminated hosts. The authors concluded that oocytes require a specific intra-follicular steroid environment for the completion of the full maturation process. Alterations to the steroid profile during maturation induce changes in the oocyte which are expressed as gross abnormalities at fertilization Moor et al.
Similarly, in other study, oocytes were collected by aspiration of preovulatory follicles from 55 women. After collection and culture, the oocytes were inseminated with the spermatozoa of the husband. A multivariate analysis containing these three hormone levels together with two ratios of progesterone with each of the other hormones indicated reasonable discrimination between the oocytes which fertilized and those which remained unfertilized after insemination.
More recently, an academic article presents the result of a study on the correlation among sex steroids in follicular fluid FF and cultured granulosa cells and fertilization. The study examined the levels of E2, P4, and T in follicular fluid from stimulated cycles and their granulosa cell cultures after oocyte retrieval and the correlation between these levels. It revealed that there is no link among fertilization and sex steroid levels in FF and granulosa cells FertilityWeekly, This is an important recent report taking in account that now a day in some in vitro fertilization —IVF- protocols, sexual steroids are commonly used as factor of fertilization improvement.
Also, high follicular fluid E2 may be a marker for oocytes that will fertilize normally with intracytoplasmic sperm injection ICSI Lamb et al. At the spermatozoa level, in human it was demonstrated the expression of a functional surface estrogen receptor of 29 KDa. Luconi et al. The ontogeny and functional role of steroidogenesis during mammalian gestation is poorly understood. A review provides a summary of findings on the spatio-temporal expression of key steroidogenic genes controlling progesterone synthesis in the uterus during mouse pregnancy.
This unexpected early expression of the enzymes in the maternal decidua is terminated at mid-pregnancy when the steroidogenic ability reappears in the extraembryonic giant cells at the time of placentation. The giant cells express the StAR protein. Unlike the human placenta, the steroidogenic genes are not expressed in the cells of the mature mouse placenta during the second half of gestation.
It was proposed that the local production of progesterone acts as an immunosuppressant at the materno fetal interface preventing the rejection of the fetal allograft Ben-Zimra et al. Strauss III et al. In some mammals, the placenta eclipses the pituitary in the maintenance of ovarian function e. In human and in sheep, horse, cat, and guinea pig, the placenta acquires the ability to substitute for the ovaries in the maintenance of gestation at various times during pregnancy.
They noted that even though the placentae of other species cannot substitute for ovarian function, all placentae critically studied expressed steroidogenic enzymes. Therefore, the ability to elaborate or metabolize steroid hormones is one common feature of trophoblast cells despite the marked differences in placental morphologies.
In human, rhesus monkey, baboon, and horse, the placenta does not express 17a-hydroxylase. Placental estrogen synthesis in these species depends upon a source of androgen precursor from the fetus; the fetal adrenal glands in the case of primates, the gonadal interstitial cells in the case of the horse. In contrast, the trophoblast cells of rat, pig, sheep and cow express 17a-hydroxylase and are able to synthesize androgens and in some species estrogens.
In the rat, estrogen, synthesized by the ovaries, suppresses placental expression of 17a-hydroxylase. Since the rat placenta elaborates androgens that are potential precursors for ovarian aromatization, a dialogue between the placenta and ovary may take place in this species. Estrogens not only regulate 17a-hydroxylase expression, they control placental mass.
The rat placenta hypertrophies in response to ovariectomy, and this hypertrophy is blocked by exogenous estrogen. These findings support the notion of an ovarian-placental interaction Strauss et al. Since , Meinecke-Tillnann et al. Increasing plasma levels of estrone sulphate and E2 were determined during the last ten days preceding parturition. Both estrogen concentrations remained constant during the puerperium until day 51 post partum Meinecke-Tillrnann et al.
This complete described estrogene pattern is now a day well understood. Fetal cortisol promotes the synthesis of three enzymes that convert P4 to E2. Progesterone, that is high at the placenta interface from gonadal or placental origin depending on the species, as explained before , is converted to 17 alpha-hydroxy-P4 by the enzyme 17alpha-hydroxylase. Fetal cortisol also induce the production of desmolase to produce androstenedione from the 17 alpha-hydroxy-P4 and then the induced enzyme aromatase converts androstenedione to estrogens; that is at the end a dramatic drop in P4 and a dramatic elevation in E2.
The consecuences are that myometrium becomes increasingly more active and displays noticeable contractions. At the same time, fetal cortisol induces placental production of PGf2a which initiates the luteolytic process, contributing to the decrease of gonadal P4 production. Sex steroids and oxytocin OT produced within intrauterine tissues have been implicated in the regulation of parturition. Fang et al. Serum P4 declined after day 19, and uterine PR did not change significantly.
Uterine PGE2 increased progressively, reaching peak levels the evening before delivery. Uterine OTR did not increase until the morning of delivery, and uterine OT peptide concentrations increased only during parturition. Parturition was significantly delayed by 24 h in the TAM-treated group. The precise temporal control of uterine contractility is essential for the success of pregnancy. For most of pregnancy, progesterone acting through genomic and non-genomic mechanisms promotes myometrial relaxation.
Steroid hormone control myometrial contractility and parturition as part of the parturition cascade. Mesiano and Welsh, The compulsory progesterone withdrawal necessary for deliveru take place is mediated by changes in myometrial expression of progesterone receptors PRs -a and —b. This withdrawal in human parturition may be mediated by an increase in the myometrial PR-a to PR-b ratio due to increased PR-a expression affecting myometrial cell progesterone responsiveness Merlino et al.
In domestic animals, puerperium begins immediately after parturition and lasts until reproductive function in restored so that another ovulation occurs and other potential pregnancy can take place. The time required for complete uterine repair and ovarian activity to resume in the postpartum female varies significantly among species beef cows: 30d and d; dairy cows: d and 25d; ewe: 30d and d; mare: 28d and 12 d; sow: 30d and 7d; queen: 30d and 30d; bitch: 90d and d, a long natural postpartum anestrus.
In beef cow, sows and women, the lactation inhibits ovarian activity Senger, Also, manipulation of abnormal anestrus in ruminants with sex steroids implants P4,E2 , intra muscular or intravaginal devices during postpartum are intended in order to shortening or at least to be near the normal period required to re-produce. In beef cows zebu-Bos indicus cattle , in some environmental conditions, the interval parturition-ovarian reactivation anestrous period and the abnormal sex steroids production represent a big economical problem d, vs.
This was investigated many years ago in the follicular morfological and steroids dynamics aspects concluding about very individual patterns and about the potential early capacity of initiating ovarian activity depending on many factors Ruiz-Cortes and Olivera-Angel, The return to the ovarian activity postpartum, is determined by the recovery of the hipotalamic-hipofisis-ovary axis and mainly by three factors: a nutrition, by the secretion of leptin from adipocites, b suckling, by prolactin production and c the cow-calf link, mediated by the senses of the vision and smell.
In addition, after ovarian recovery postpartum, the cows present low fertility associated with corpus luteum of short duration and low production of P4. The induction of estrus with progestins has generated corpus luteum of normal duration, in response to the weaning or to the injection of gonadotrophins.
Zebu cows postpartum, were treated with progestins and with temporal suckling interruption TSI :calves-cows separation, for 72 hours. We could conclude that the treatment with TSI solely or in combination with progestins, can induce estrus, ovulation and corpus luteum of good quality, in postpartum Zebu cows. This useful tool for shortennig calving intervals is now a day used with success by local farmers Giraldo Echeverri et al.
Those features indicate mainly the multifactorial effects of the peripartum on the sex steroids production, but also the gonadal steroids important role in the pospartum cyclicity reactivation. High levels of E2 near the delivery and some days after are also regulating the OTR expression and the OT and effects myometrium.
Thus contractions needed for the placenta membranes and lochia blood-tinged fluid containing remnants of the fetal placenta and endometrial tissue discharge in the early postpartum occurs Table 2. Studies in primates have suggested that pre- and peripartum sex steroid hormones may be important determinants of maternal behavior and motivation, since higher levels of prepartum estrogen are associated with maternal competency and infant survivorship. The researchers found that high concentrations of prepartum E 2 in callitrichid primates are not necessarily associated with competent maternal behavior and may instead be associated with poor infant survivorship and inadequate maternal care.
That appears to be convergent with research focusing on human mothers and may represent a common underlying mechanism linking prepartum estrogen and postpartum affect and behavior in some primates. Similary, in males of this specie, T, and possibly E2, play an important role in balancing the expression of paternal care with that of other reproductive behavior Fite and French, ; Nunes et al.
The importance of the sex steroid hormones E2 and P4 for normal development of the mammary gland was recognized several decades ago and has been unequivocally confirmed since. This influence is not restricted to mammogenesis, but these hormones also control involution. Lamote et al. Nevertheless, in a model of in vitro mammary gland involution mammary epithelial cells —MEC where authors were interested in the autophagy and the apoptosis occurring during involution, they concluded about important molecular pathways explaining the sex steroids-growth factors cross-talk during lactation and involution.
They investigated the effects of insulin-like growth factor-1 IGF-I and epidermal growth factor EGF signaling, as well as sex steroids on autophagy focusing about the role regulatory role of mTOR. In conclusion, autophagy in bovine MEC undergoes complex regulation, where its activity is controlled by survival pathways dependent on IGF-I and EGF, which are involved in suppression of autophagy, and by pregnancy steroids, which act as inducers of the process Sobolewska et al.
Probably mammogenesis is also regulated by similar kinase pathway, and this is a clue finding to better understand sex regulation of mammalian lactation Table 2. Ovarian steroids E2 and P4 diffuse directly from the blood into milk by passive diffusion because they are lipid soluble. All steroids hormones can be found in milk. The concentration of E2 and P4 in milk reflects cyclic hormone production by the ovaries and is highly correlated with blood concentrations.
Such a phenomenon enables steroids particulary P4 to be easely assayed in milk to determine the reproductive status of the female. The development of such technology would enable the producer to determine whether a cow is cycling, the stage of estrous cycle, pregnancy status and some form of ovarian pathology v.
Menopause is preceded by a period of menstrual cycle irregularity, known as the menopause transition or peri-menopause, which usually begins in the mids. The menopause transition is characterized by many hormonal changes predominantly caused by a marked decline in the ovarian follicle numbers. Accordingly, it has been reported that the decrease in estrogen contributes to the decrease in bone mass density, the redistribution of subcutaneous fat to the visceral area, the increased risk of cardiovascular disease and the decrease in quality of life.
In addition, hormonal changes may also have a direct effect on muscle mass. The measurement of urinary estrogens metabolites could add new evidence as for the role of estrogens in sarcopenia. It remains certain, though, that the decline in muscle mass is associated with an increased risk of functional impairment and physical disability. Finally, further randomized controlled trials are needed to investigate the effects of physical activity as well as hormone and phytoestrogen supplementation on sarcopenia Messier et al.
A recent review of literature from until , compare oral and transdermal delivery systems for postmenopausal estrogen therapy in domains of lipid effects; cardiovascular, inflammatory, and thrombotic effects; effect on insulin-like growth factor, insulin resistance, and metabolic syndrome; sexual effects; metabolic effects including weight; and effects on target organs bone, breast, and uterus.
Significant differences appear to exist between oral and transdermal estrogens in terms of hormonal bioavailability and metabolism, with implications for clinical efficacy, potential side effects, and risk profile of different hormone therapy options, but as neither results nor study designs were uniform, not complete conclusions could be done. Weight gain appears to be slightly lower with a transdermal delivery system.
Oral estrogen's significant increase in hepatic sex hormone binding globulin production lowers testosterone availability compared with transdermal delivery, with clinically relevant effects on sexual vigor Goodman, In contrast, research into andropause has only recently begun. Furthermore, evidence now suggests that steroidogenesis is not restricted to the gonads and adrenals, and that the brain is capable of producing its own steroid hormones, including testosterone and estrogen Bates et al.
Male aging is associated with a variable but generally gradual decline in androgen activity, which can manifest as sexual dysfunction, lethargy, loss of muscle and bone mass, increased frailty, loss of balance, cognitive impairment and decreased general well-being, such as depression and irritability. Andropause is defined as the partial or relative deficiency of androgens and characteristic associated symptoms.
These symptoms suggest that androgens may have an important modulatory role in cognition and mental health. Indeed memory loss was the third most common reported symptom of andropause, after erectile dysfunction and general weakness in a survey of elderly men Bates et al. Mild cognitive impairment MCI is becoming fashionable as a diagnosis, representing a state of cognitive decline associated with negligible functional loss.
Many patients in transition into andropause report problems with their memory. There is strong evidence from basic sciences and epidemiological studies that both estrogens and androgens play a protective role in neurodegeneration. The evidence from small prospective clinical trials lends support to the role of hormones in improving cognitive function. Patients have reported memory improvements in both declarative and procedural domains after being on hormonal replacement.
Authors have hypothesized androgens and perhaps selective androgen receptor modulators as future treatment options for MCI in aging males Tan et al. Gonadal steroids regulation of clue reproductive moments. Definitions, target tissues and main sex steroids effects.
Since the adipose tissue hormone leptin was discovered in , its energy balance regulatory effects have been well investigated and accepted. The interaction of leptin and its membrane receptors within different systems were also the focus of interest of many researches making the protein and the receptor almost ubiquitous in mammals. Thus, it is of big interest the relationship of leptin with sex steroids. Although gonadal steroids, unlike leptin, are clearly not critical to the maintenance of normal energy homeostasis, they do appear to function as physiologic modulators of this process.
Gonadal steroids influence food intake and body weight. Although the specific mechanisms underlying these effects are not clear, a consideration of their effects in the context of current models of energy homeostasis may ultimately lead to the identification of these mechanisms.
When compared with leptin, the prototypical humoral signal of energy balance, sex steroids share many common properties related to food intake and body weight. Specifically, gonadal steroids circulate in proportion to fat mass and current energy balance, and administration of these compounds influences food intake, energy expenditure, body weight, and body composition.
Moreover, both estrogens and androgens modulate central nervous system effectors of energy homeostasis that are targets for the action of leptin, including pathways that contain neuropeptide Y, pro-opiomelanocortin, or melanin-concentrating hormone Mystkowski and Schwartz, Several studies have reported decreased circulating estradiol levels in type 1 and type 2 diabetic animal models.
Women with type 1 diabetes experience decreased sexual arousal function and have significantly reduced E2 levels compared to control subjects. Limited data are available in type 2 diabetic women. It was proposed that diabetes disrupts estrogen signaling. This hypothesis was partially supported by studies showing that E2 supplementation in diabetic animals ameliorates some of the diabetic complications in several organs and tissues, including those that control anabolic and catabolic pathways food intake and energy expenditure such as melanocortin in the hypothalamic arcuate nucleus and neurons containing neuropeptide Y.
No studies are available on the therapeutic effects of estradiol supplementation in type 2 diabetic animals in ameliorating the changes in sex steroid receptor expression and tissue localization and distribution. The percentage of body fat increased in groups receiving placebo or 1. Lean mass and thigh-muscle area decreased in men receiving placebo and in those receiving 1. Leg-press strength fell only with placebo administration.
In general, sexual desire declined as the testosterone dose was reduced. The study showed that the amount of testosterone needed for maintenance of lean mass, fat mass, strength, and sexual function varied widely; however the current diagnosis of androgen deficiency relies on a single measure of testosterone 2SD below the mean in normal young men. Androgen deficiency accounted for decreases in lean mass, muscle size, and strength; oestrogen deficiency primarily accounted for increases in body fat; and both contributed to the decline in sexual function.
The clinical implications of the study suggest a change in the evaluation and management of hypogonadism in men. You are here Research reviews. Aim The study was designed to suppress endogenous testosterone and then add back one of four different doses of testosterone or placebo , with half also receiving an aromatase inhibitor to block synthesis of oestradiol. Methods The study included healthy men 20 to 50 years of age with normal serum testosterone levels.
Modified intention-to-treat statistical analyses were done. Results There was some loss to follow-up in both cohorts: the men not given cohort 1 and the men given cohort 2 aromatase inhibitors. Conclusion The study showed that the amount of testosterone needed for maintenance of lean mass, fat mass, strength, and sexual function varied widely; however the current diagnosis of androgen deficiency relies on a single measure of testosterone 2SD below the mean in normal young men.
Points to Note This study makes a significant contribution to understanding the degree of hypogonadism in men at which adverse changes occur and the role of androgens and oestrogens in specific outcomes. The finding that oestrogen deficiency is largely responsible for some of the main consequences of androgen deficiency suggest that measuring oestradiol may be helpful in assessing risk of fat accumulation or sexual dysfunction.
The study was limited by a relatively short follow-up 16 weeks whereby the possible longer term effects of the higher dose testosterone may have been missed.
Subcutaneous and intra-abdominal fat areas measured by CT , thigh muscle area measured at mid-femur and strength leg press weight , and sexual function measured with HR-QOL questionnaire and divided into erectile function and sexual desire were secondary outcomes. There was some loss to follow-up in both cohorts: the men not given cohort 1 and the men given cohort 2 aromatase inhibitors.
Numbers included in analyses of various outcomes ranged from to in cohort 1 and to in cohort 2. The percentage of body fat increased in groups receiving placebo or 1. Lean mass and thigh-muscle area decreased in men receiving placebo and in those receiving 1. Leg-press strength fell only with placebo administration.
In general, sexual desire declined as the testosterone dose was reduced. The study showed that the amount of testosterone needed for maintenance of lean mass, fat mass, strength, and sexual function varied widely; however the current diagnosis of androgen deficiency relies on a single measure of testosterone 2SD below the mean in normal young men.
Androgen deficiency accounted for decreases in lean mass, muscle size, and strength; oestrogen deficiency primarily accounted for increases in body fat; and both contributed to the decline in sexual function. The clinical implications of the study suggest a change in the evaluation and management of hypogonadism in men. You are here Research reviews. Aim The study was designed to suppress endogenous testosterone and then add back one of four different doses of testosterone or placebo , with half also receiving an aromatase inhibitor to block synthesis of oestradiol.
Methods The study included healthy men 20 to 50 years of age with normal serum testosterone levels. Modified intention-to-treat statistical analyses were done. Results There was some loss to follow-up in both cohorts: the men not given cohort 1 and the men given cohort 2 aromatase inhibitors.
Conclusion The study showed that the amount of testosterone needed for maintenance of lean mass, fat mass, strength, and sexual function varied widely; however the current diagnosis of androgen deficiency relies on a single measure of testosterone 2SD below the mean in normal young men. In addition, administration of leptin to rodents increases sexual behavior in fed, but not in food-deprived, female hamsters These observations are consistent with the hypothesis that leptin functions as an afferent signal regarding somatic energy stores that influences reproductive activity and behavior to synchronize endocrine and behavioral components of reproductive function with the sufficiency of energy stores.
The influences of adipose tissue mass and estrogen on circulating concentrations of leptin would signal that females were both nutritionally and endocrinologically prepared for reproduction. The apparent decrease in leptin sensitivity in response to increased estrogen might function to encourage increased energy intake during pregnancy, lactation, or periods of maximum fertility in preparation for pregnancy.
Evolutionary pressures select for or against the prevalence genes by affecting the likelihood of reproductive efficiency and the survival of progeny. Longevity beyond the reproductive years should not be subjected to such selection pressures, except insofar as having a surviving parent increases the likelihood of the survival of existing offspring.
These principles are clearly evident in the sexual dimorphism of body habitus between male and female humans. Genes favoring mobility, strength to compete with other males for mating privileges, and aggressiveness during periods of maximum fertility adolescence in males and estrus in females would presumably be selected for in males.
Both genders would benefit from genes tending to enhance the ability to store excess calories as fat. Because such a tendency would have enabled our distant progenitors to survive periods of prolonged caloric deficiency, it is likely that the human genome would be heavily enriched with such genes. Survival advantages related to genetic predisposition to storage of calories as fat would be greater in women than in men because women are subjected to the additional energy demands of sustaining gestation and of breastfeeding offspring but are less subject than males to selection pressures favoring increased strength, mobility, and aggressiveness.
Leptin integrates systems of energy homeostasis with those controlling the hypothalamic-pituitary-gonadal axis. There are complex reciprocal interactions of these processes so that leptin affects the integrity of the gonadal axis, and the gonadal steroids affect both leptin production and sensitivity. Pregnancy and lactation are examples of periods in the life cycle when it is desirable to increase energy intake and adipose tissue mass.
Perhaps placenta-driven increases in circulating estrogen raise the central nervous system threshold to ambient leptin in the gravid female. N Engl J Med. Google Scholar. Kennedy G. Proc R Soc Biol Sci. Rosenbaum M , Leibel R. Trends Endorcinol Metab. Legato M. Int J Fertil Womens Med. Norgan N. Int J Obesity. J Clin Endocrinol Metab. J Endocrinol. Am J Clin Nutr.
Am J Physiol. Annu Rev Nutr. Heymsfield SB , Waki M. Nutr Rev. Lukaski HC. Kroger H , Reeve J. Ann Med. Scheiber L , Torregrosa L. Semin Arthritis Rheum. Am J Cardiol. Am J Epidemiol. Bjorntorp P. Stromblad G , Bjorntorp P.
J Clin Invest. Eur J Clin Invest. Hum Reprod. Philadelphia : Saunders. Obesity Res. Biochem Mol Biol Int. Frisch R , Revelle R. Frisch R. Perspect Biol Med. Neuroendocrinology 65 : — Brain Res Mol Brain Res. Brain Res. Nat Med. Horm Metab Res 28 : — Ellis K , Nicolson M. Pediatr Res.
J Pediatr. Troen P , Oshima H. Endocrinology and metabolism. New York : McGraw-Hill; — Speroff L. Clin Endocrinol Oxf. Horm Res. Rising leptin levels may signal the onset of puberty. J Biol Chem. Acta Physiol Scand.
N Eng J Med. Coleman DL. Nat Genet. Mamm Genom. Spicer L , Francisco C. Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide. Sign In or Create an Account. Sign In. Advanced Search. Search Menu.
Skip Nav Destination Article Navigation. Close mobile search navigation Article Navigation. Volume Article Contents Body composition. Sexual dimorphism in circulating concentrations of leptin. Leptin, body composition, and energy homeostasis. Body composition, leptin, and fertility. Article Navigation.
Oxford Academic. Rudolph L. Select Format Select format. Permissions Icon Permissions. Body composition Absolute measures of body fat or water content fat mass and fat-free mass must be distinguished from measures of fractional body fat body fatness calculated as the ratio of fat mass to total body weight or from various permutations of the relationship between weight and height [ e. Sexual dimorphism in circulating concentrations of leptin Initial reports of circulating leptin concentrations in humans suggested that, for a given level of body fatness BMI , leptin concentrations were significantly greater in women than in men Leptin, body composition, and energy homeostasis The hyperphagia, hypometabolism, decreased thermogenesis, and hypothyroidism of the leptin-deficient or leptin-resistant rodent recapitulate the metabolic adaptations of humans to hypocaloric intake 1 , 78 , Body composition, leptin, and fertility Frisch et al.
Perspectives Evolutionary pressures select for or against the prevalence genes by affecting the likelihood of reproductive efficiency and the survival of progeny. Google Scholar Crossref. Search ADS. The role of depot fat in the hypothalamic control of food intake in the rat. Leptin: a molecule integrating somatic energy stores, energy expenditure, and fertility. Effects of gender, body composition, and menopause on plasma concentrations of leptin. Google Scholar PubMed. Effects of weight change on plasma leptin concentrations and energy expenditure.
Estrogen increases in vivo leptin production in rats and human subjects. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: executive summary. Organ-tissue mass measurement allows modeling of REE and metabolically active tissue mass. Body composition in humans: advances in the development of multicompartment chemicals models.
Human body composition: comparison of two improved four-compartment models that differ in expense, technical complexity and radiation exposure. Methods for the assessment of human body composition: traditional and new. Dual-energy x-ray absorptiometry body composition model: review of physical concepts. Waist circumference and abdominal sagittal diameter: best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women.
Body size and fat distribution as predictors of coronary artery disease among middle aged and older US men. Fatty acids in the portal vein of the rat regulate hepatic insulin clearance. Sex differences in the relation of visceral adipose tissue accumulation to total body fatness.
Identification of progesterone receptor in human subcutaneous adipose tissue. Identification of oestrogen receptors and oestrogen receptor mRNA in human adipose tissue. Regional differences and up-regulation of progesterone receptors in adipose tissue from oestrogen-treated sheep. Serum leptin in obese women with polycystic ovarian syndrome is correlated with body weight and fat distribution but not with androgen and insulin levels. Long-term testosterone administration increases visceral fat in female-to-male transsexuals.
Exogenous androgens influence body composition and regional body fat distribution in obese post-menopausal women—a clinical research center study. Are gender differences in cardiovascular disease risk factors explained by the level of visceral adipose tissue? Relationship of body fat distribution to reproductive factors in pre- and postmenopausal women. Effect of chronic intravenous injection of steroid hormones on body weight and composition of female rats.
Height and weight at menarche and a hypothesis of critical body weights and adolescent events. Ontogeny of region-specific sex differences in androgen receptor messenger ribonucleic acid expression in the rat forebrain. Androgen receptor and mating-induced Fos immunoreactivity are co-localized in limbic and midbrain neurons that project to the male rat medial preoptic area. Immunocytochemical localization of androgen receptors in brains of developing and adult rhesus monkeys.
Leptin levels in human and rodents: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Sex differences in circulating human leptin pulse amplitude: clinical implications. Effects of gender, ethnicity, body composition, and fat distribution on serum leptin levels in children. Visceral fat accumulation in obese subjects: relation to energy expenditure and response to weight loss.
Depot- and sex-specific differences in human leptin mRNA expression: implications for the control of regional fat distribution. Serum leptin concentrations in cord blood: relationship to birthweight and gender. Leptin levels and body fatness in children: effects of gender, ethnicity, and sexual development.
CAG, but lower levels of Roseburia sp. CAG, Succinivibrio dextrinosolvens , Clostridium sp. At the family level, men had higher Pasteurellaceae , Cytophagaceae , Idiomarinaceae , Prevotellaceae , Sphingobacteriaceae , Flavobacteriaceae , and Fibrobacteriaceae , whereas the abundance of Synergistaceae , Fusobacteriaceae , Myxococcaceae , Actinobacteria , Enterococcaceae , and Christensenellaceae was higher in pre-menopausal women Supplementary Figure 1 a.
Once again, men had higher abundances of Fibrobacteriaceae and Sphingobacteriaceae compared to post-menopausal women, whereas the latter had higher levels of Acetobacteriaceae , Leuconostocaceae , Acholeplasmataceae , Lactobacillaceae , Streptococcaceae , and Lentisphaerae Supplementary Figure 1 b. Post-menopausal women had higher abundances of Pasteurellaceae , Comamonadaceae , and Lentisphaerae , but lower abundances of Acholeplasmataceae , Enterococcaceae , Micrococcales , and Christensenellaceae than pre-menopausal women Supplementary Figure 1 c.
Metagenome functional analyses based on KEGG pathways revealed significant differences between premenopausal women and men Fig. Remarkably, enrichment in steroid biosynthesis and degradation of metabolic pathways were found in the gut microbiota of premenopausal women compared to men.
Other differentially expressed pathways included arginine biosynthesis and metabolism, purine and pyrimidine metabolism, one carbon pool by folate and carbohydrate metabolism pathways. Conversely, we did not find significant differences in the microbiome functionality between postmenopausal women and men, despite having different bacterial composition. In line with the functional differences between premenopausal women and men, the gut microbiota of premenopausal women was enriched in pyrimidine and one carbon pool by folate pathways compared to postmenopausal women Fig.
In addition, these differences were blunted by obesity. Therefore, while these functional differences between premenopausal women and men and between pre- and postmenopausal women were evident in non-obese individuals Supplementary Figure 2 a,b , no differences in the gut microbiota functionality were observed in obese subjects. Finally, most of the identified bacterial pathways had significant correlations with the plasma levels of gonadal steroids, particularly progesterone and testosterone Fig.
Interestingly, after adjustment for age, obesity, and menopause status, the steroid degradation pathway had a significant positive correlation with progesterone levels. Associations of gut microbiota functionality with gender and menopause status.
Clustering was based on Euclidean distances and Ward linkage. Significant associations after adjusting for age, obesity, and sex are highlighted with a black box. Unsupervised analyses by principal component analysis also showed a clear between-group difference Fig. Remarkably, most of these differences were lost in obese subjects Supplementary Figure 3.
In addition, estrogens levels were higher in obese post-menopausal women compared to lean post-menopausal women, whereas no differences were found between obese and lean pre-menopausal women. This is in agreement with the fact that pre-menopausal women mainly synthesize estrogens in the ovary, while in post-menopausal women ovarian biosynthesis is replaced by peripheral site synthesis, and in obese postmenopausal women, adipose tissue is the main source of estrogen biosynthesis.
Gender and menopausal status differences in gonadal steroids. Differences among groups were analyzed by a Kruskal-Wallis test, and pair-wise comparisons were assessed by Wilcoxon test. Significant differences are highlighted in bold. We then evaluated the possible associations between gut microbiota composition and the circulating concentrations of the main gonadal steroids.
In particular, Prevotellaceae , Cytophagaceae , Fibrobacteriaceae , Sphingobacteriaceae , and Idiomarinaceae were positively associated with testosterone levels, whereas several families from the Actinobacteria, Proteobacteria, Firmicutes, and Verrucomicrobia phylum were negatively associated with testosterone levels. We further evaluated the association between the gut microbiota families and the circulating testosterone levels using a negative binomial distribution by DESeq2 and adjusting for age and obesity Fig.
Again, Fibrobacteriaceae , Idiomarinaceae , and several families from the Bacteroidetes phylum Sphingobacteriaceae , Cytophagaceae , Prevotellaceae , and Flavobacteriaceae still had positive associations with testosterone levels, whereas Acholeplasmataceae , Verrucomicrobia, and several families from the Proteobacteria Gammaproteobacteria , Myxococcaeae , Xanthomonadacea , Firmicutes Lactobacillaceae and Actinobacteria phyla had the strongest negative fold change.
Gut microbial associations with circulating testosterone concentrations. Pairwise differences between groups were assessed using the pairwise. Noteworthily, the same bacterial family signature was still positively associated with testosterone levels in non-obese subjects, whereas Verrucomicrobia and Akkermansiaceae also from Verrucomicrobia phylum were predictive of lower circulating testosterone concentrations.
In particular, we identified a consistent microbial signature positively associated with testosterone concentrations that included Cytophagaceae , Prevotellaceae , Fibrobacteriaceae , Sphingobacteriaceae , Flavobacteriaceae , and Idiomarinaceae Supplementary Figure 4 d. Once again, several families from the Verrucomicrobia, including Optitutaceae , Puniceicoccaceae , and an unknown family of Verrucomicrobia, have negative associations with testosterone.
We finally evaluated the hypothesis that the sex-related signature could be transplanted to mice through the gut microbiota. We transplanted the microbiota from 11 men and 11 women age and obesity matched to 22 male mice Fig. Remarkably, most mice receiving microbiota from obese post-menopausal women had a microbiota profile similar to those that received microbiota from male donors Fig. Specifically, Sphingobacteriaceae , Fibrobacteriaceae , Prevotellaceae , Cytophagaceae, Idiomarinaceae , Flavobacteriaceae , Eggerthellaceae , Ruminococcaceae , Marinifilaceae , Deltaproteobacteria , and Sporomusaceae were positively associated with testosterone in both mice and humans, whereas Verrucomicrobia and Enterobacteriaceae had negative associations.
Akkermansiaceae was also negatively associated with human donor testosterone in mice and non-obese subjects. Sexual dimorphism has long been associated with health and disease [ 20 ]. For example, men are at higher risk of CVD than premenopausal women, but this cardioprotection is lost after menopause [ 21 ], suggesting the contribution of gonadal steroids on susceptibility to disease.
More recently, the gut microbiota has also been implicated on the etiology of several diseases [ 22 , 23 , 24 ]. Therefore, the gut microbiota may be the driving force underlying the observed sexual dimorphism in disease susceptibility. There is some evidence to support that the gut microbiota differs between sex, although the results are inconsistent [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 12 , 15 ], partly because sexual dimorphism in the gut microbiome may also be influenced by diet, age, obesity, ethnicity, and genotype [ 6 ].
The findings of the current study confirm some of the previous observations, with higher abundances of Prevotella and Fusobacterium species in males, and of Alistipes , and Lachnospiraceae bacterium species in females. In addition, non-obese women also had higher abundances of several Akkermansia species compared to non-obese men.
Importantly, the majority of the studies did not consider menopausal status as a potential confounding factor. Interestingly, we found that the number of species from genera differentiating men and women was lower after menopause. We also found that premenopausal women had higher abundances of several Alistipes , Bifidobacterium , and Ruminococcus species but lower abundances of Bacteroides , Prevotella , and Haemophilus species compared to postmenopausal women and men.
Therefore, our results suggest a masculinization of the gut microbiota composition after menopause. This androgenization of the microbiome was further corroborated by functional analyses. Therefore, while we found several differentially abundant bacterial pathways between premenopausal women and men, only the arginine biosynthesis and metabolism pathway differed between the postmenopausal and men microbiome.
This pathway was enriched in women independently of menopausal status compared to men. It is one of the central pathways for the biosynthesis of arginine, a precursor of nitric oxide NO , which plays a key role in the regulation of blood pressure. In fact, Forte et al. This could partly explain the substantial sex differences observed in hypertension from epidemiological studies [ 23 ].
Consistently, alterations in the arginine and proline metabolism have been reported in individuals at high risk of CVD [ 26 ] and spontaneously hypertensive rats [ 27 ]. We also found a consistent enrichment in the one-carbon pool by folate pathway in the microbiome of pre-menopausal women compared to post-menopausal women and men. Folic acid is the most important determinant of homocysteine levels, whose levels have been related to CVD [ 28 ]. Notably, men and post-menopausal women have higher homocysteine levels and are at higher risk of CVD compared to pre-menopausal women [ 29 , 30 ].
Interestingly, we found that pre-menopausal women had higher abundances of Lactobacillus plantarum compared to post-menopausal women and men. Unlike other Lactobacillus species, L. On the other hand, a limited number of studies have shown that the sex difference in the gut microbiota is influenced by the grade of obesity [ 12 , 16 ].
Accordingly, we found significant differences in the gut microbiota functionality between non-obese premenopausal women and men, but no differences were observed in obese subjects. In addition, none of these studies have taken into account the menopausal status. Similarly, we found that the functional differences in the gut microbiota between pre- and post-menopausal women disappeared in obese women.
Therefore, obesity has the effect of erasing the sexual dimorphism associated with the microbiome. Low levels of several plasma steroids, including testosterone and hydroxyprogesterone, have been associated with higher adiposity and visceral fat [ 32 ]. These two steroid hormones were precisely among those that did differ between non-obese pre- and post-menopausal women, but not between obese individuals.
Due to the relationship between gonadal steroids and the gut microbiome, it is possible that a decreased production of steroid hormones in obese subjects partly explains the lack of sexual dimorphism in the gut microbiota of these individuals. There is evidence that some bacterial species are able to metabolize and catabolize estrogen and androgens and their precursors, thereby affecting their systemic levels [ 33 , 34 , 35 ]. For example, bacteria possess several enzymes involved in the steroid biosynthesis and metabolism such as hydroxysteroid dehydrogenase HSD.
Notably, we found that the gut microbiota of pre-menopausal women was more enriched in steroid biosynthesis and degradation pathways and these microbial pathways had significant associations with the plasmatic levels of testosterone and progesterone.
HSD is abundant in species of the Actinobacteria phylum, specifically in Bifidobacterium species [ 36 ], and Proteobacteria and Firmicutes phyla [ 37 ]. Interestingly, we found that premenopausal women had higher abundances of Actinobacteria species, and in particular several Bifidobacterium species, compared to men. In addition, we found that several families from the Actinobacteria, Proteobacteria, and Firmicutes phyla were predictive of lower testosterone circulating concentrations.
In line with the ability of the gut microbiota to modulate steroid levels, animal models demonstrate that the microbiome is essential in maintaining regular estrogen cycles, testosterone levels, and reproductive roles in both sexes. Germ-free non-obese diabetic male mice had lower testosterone concentrations than conventional mice [ 38 ]. In addition, removal of the microbiota increased the circulating testosterone concentration in female mice but decreased the levels in male mice [ 38 ].
The negative associations between the relative abundance of some bacterial species and serum testosterone levels are in line with its removal leading to increased circulating testosterone in females. In turn, the microbiome may be affected by hormone levels.
Previous investigations have focused on the influence of estrogen on microbiota composition [ 39 , 40 , 41 , 42 , 43 , 44 , 45 ]. For example, the relative abundance of Bacteroidetes was significantly increased in an ovariectomized rat model [ 46 ]. In another study, normal females had significantly lower Proteobacteria abundance and Firmicutes to Bacteroidetes ratio, but higher Bifidobacterium to Enterobacteriaceae ratio and increased Akkermansia abundance, compared to normal male and ovariectomized OVX females [ 45 ].
Treatment with progesterone in OVX mice resulted in a significant change in the gut microbiota composition, with particular increases in Lactobacillus species [ 47 ]. In women, the relative abundance of the Gammaproteobacteria class and an unknown family from Myxococcales correlated positively with estradiol levels, while Prevotellaceae had a negative correlation [ 13 ].
Consistently, we found that Prevotellaceae family was positively associated with testosterone levels, whereas Gammaproteobacteria , Lactobacillaceae , and Myxococcaceae had negative associations. Post-menopausal women did not exhibit higher levels of testosterone than pre-menopausal women suggesting that a mechanism other than androgenization may be also responsible for the differences in gut microbiota between pre-menopausal women vs. Only a few studies reported the associations between the gut microbiota and testosterone.
Prenatal exposure to testosterone cypionate in female rats resulted in a lower abundance of Akkermansia , Bacteroides , Lactobacillus , and Clostridium in adult female offspring [ 48 ]. Gonadectomy along with a high fat diet was associated with increased genera of Ruminococcaceae family in male mice of three different strains and reduced Akkermansia genus in female mice [ 49 ]. However, males on a chow diet had higher Ruminococacceae than females.
An indirect way to consider the effects of testosterone levels is through women or animal models of polycystic ovary syndrome PCOS , which is characterized by an excessive production of androgens or testosterone. In female rats, the increase in testosterone after Letrozole-induced PCOS led to decreased Lactobacillus , Ruminococcus , and Clostridium , but higher Prevotella [ 51 ].
Letrozole treatment of adult mice also resulted in a higher relative abundance of genera from Lachnospiraceae , Ruminococcaceae , and Peptococcaceae , and lower Lactobacillus [ 52 ]. In a recent human study, Bacteroidetes, Firmicutes, and Verrucomicrobia phyla differed between women with PCOS and controls, with obesity having a driving role in the development of dysbiotic microbiota [ 53 ].
In line with these results, in the current study, the abundance of some Lachnospiraceae bacterium Firmicutes and Ruminococcus spp. Firmicutes was higher in males vs. Bacteroidetes were higher in males compared to women. We also found that non-obese women also had higher abundances of several Akkermansia spp. Verrucomicrobia compared to non-obese men. O-PLS modeling also revealed a negative association between Verrucomicrobia and Akkermansiaceae family and testosterone levels in non-obese individuals.
However, the most consistent association with testosterone in O-PLS models were with Prevotellaceae , Cytophagaceae , Ruminococcaceae , Fibrobacteriaceae , Sphingobacteriaceae, and Idiomarinaceae. However, we must point out the one limitation of the present FMT study is that only male mice were used. Although the number was small, women with PCOS did not have elevated testosterone levels when compared with the rest of premenopausal women and did not significantly influence the findings concerning testosterone levels.
The median testosterone levels in women with PCOS were 0. These women with PCOS had also low androstenedione levels compared to the other pre-menopausal women 0. In addition, we performed the KEGG metagenome functional analyses again removing these three pre-menopausal women and the results were almost the same.
In conclusion, our results evidence a clear difference in the gut microbial composition and functionality between men and women, which is influenced by both menopausal and obesity status. Therefore, menopause is proposed to induce an androgenization of the microbiome, whereas obesity overrides the sex and menopause differences observed in non-obese individuals. The gut microbiota composition was tightly linked to the circulating levels of gonadal steroids, particularly testosterone.
From January to October , a cross-sectional case-control study was undertaken in the Endocrinology Department of JosepTrueta University Hospital. JosepTrueta University Hospital Girona, Spain approved the study protocol, and informed written consent was obtained from all participants. Quantification of DNA was performed with a Qubit 3. Host reads were removed by mapping against the host reference genome, by using bowtie Next, the program Prodigal v2.
The filtering of the best annotations and the assignment of the orf annotation to every read were carried out using the statistical package R 3. In parallel, taxonomic annotation was implemented with Kaiju v1. Addition of lineage information, lineage parsing for undetermined ranks, counting of taxa, and generation of the operational taxonomic unit OTU absolute and relative abundance matrices for all samples were performed using the package R.
The loading step leads to the consequent retention of the analytes in the sorbent and the removal of sample matrix components to waste. Chromatographic separation of steroids was carried out by a Kinetex C18 analytical column particle size 2. A first gradient was applied for 3. Calibration models were prepared by analysis of aliquots of a serum pool spiked with variable concentrations of the target steroids.
Endogenous content of each steroid in the sample loop was subtracted in the preparation of the calibration models. Isotopically labeled steroids were used as internal standards for quantitative analysis of structurally similar analytes. All the experiments were performed under blinded conditions. Animals were maintained on normal mouse chow diet rat and mouse no. Food intake was the same in the two groups. At the end of the study, the animals were consecutively sacrificed.
Fecal microbiota composition from mice was analyzed following the same procedures as for humans. Results are expressed as number and frequencies for categorical variables, mean and standard deviation for normal distributed continuous variables, and median and interquartile range for non-normal distributed continuous variables. For metagenomics data, taxa were first filtered so that only those with more than 10 reads in at least two samples were selected.
It uses a generalized linear model of counts based on a negative binomial distribution, scaled by a normalization factor that accounts for differences in sequencing depth between samples. Significance testing was then assessed using the Wald test and the p values corrected for multiple comparisons by the Benjamini-Hochberg procedure p FDR [ 65 ]. In all models, age and obesity status were included as covariates.
Predications of circulating gonadal steroid levels from bacterial families were performed using orthogonal partial least squares O-PLS models with unit variance using in-house MATLAB scripts. The abundances of bacterial families after applying a variance stabilizing transformation using DESeq2 were used as the descriptor matrices X to predict the testosterone levels as the response Y.
The predictive performance Q 2 Y of each model was calculated using a tenfold cross-validation approach, and model validity was established by permutation testing permutations. Colonic microbiota signatures across five northern European countries. Appl Environ Microbiol. Differences in fecal microbiota in different European study populations in relation to age, gender, and country: a cross-sectional study.
Symbiotic gut microbes modulate human metabolic phenotypes. Human Microbiome Project Consortium T. Age-related changes in gut microbiota composition from newborn to centenarian: a cross-sectional study. BMC Microbiol. Human gut microbiome viewed across age and geography. Population-level analysis of gut microbiome variation. Science Analysis of gut metagenomes identifies sex-specific resistome profiles.
Gut Microbes. Sex, body mass index, and dietary fiber intake influence the human gut microbiome. PLoS One. Ding T, Schloss PD. Dynamics and associations of microbial community types across the human body. Differences in gut microbiota associated with age, sex, and stool consistency in healthy Japanese subjects.
J Gastroenterol. Body mass index differences in the gut microbiota are gender specific. Front Microbiol. Influence of gender and menopausal status on gut microbiota. PubMed Article Google Scholar. Sex differences in the gut microbiota as potential determinants of gender predisposition to disease. Mol Nutr Food Res. Age- and sex-dependent patterns of gut microbial diversity in human adults.
Intestinal microbiota is influenced by gender and body mass index. Effects of gender and menstrual cycle on colonic transit time in healthy subjects. Korean J Intern Med. Gastrointestinal transit: the effect of the menstrual cycle. Gender bias in autoimmunity is influenced by microbiota. Gerdts E, Regitz-Zagrosek V. Sex differences in cardiometabolic disorders.
Heart disease and stroke statistics— update. Sexual dimorphism of cardiometabolic dysfunction: gut microbiome in the play? Mol Metab. The role of the gut microbiome in sex differences in arterial pressure.
Biol Sex Differ. Sex, gut microbiome, and cardiovascular disease risk. Sex Differ. Evidence for a difference in nitric oxide biosynthesis between healthy women and men. Metabolic profiling reveals the heterogeneity of vascular endothelial function phenotypes in individuals at extreme cardiovascular risk.
RSC Adv. Royal Society of Chemistry. Establishment of the circadian metabolic phenotype strategy in spontaneously hypertensive rats: a dynamic metabolomics study. J Transl Med. Folic acid, homocysteine, and cardiovascular disease: judging causality in the face of inconclusive trial evidence.
Br Med J. Suppression of homocysteine levels by vitamin B12 and folates: age and gender dependency in the Jackson heart study. Am J Med Sci. Gambacciani M, Mannella P. However many doctors focus on the role of Testosterone as treatment for hypogonadism and place less emphasis on the role of declining estrogen. The one exception may be bone loss as it is common knowledge that very low levels of estrogen contribute to bone loss. However estrogens role on body composition and sexual function is not entirely known.
Information on the role of estrogens in male hypogonadism may help identify men at risk for specific manifestations of the condition and may provide a rationale for novel approaches to its management. From a practical perspective, men suffering from hypogonadism need to know if very low levels of estrogen may be detrimental to sexual function and if those low levels may also be negatively effecting body composition.
In addition, steroid users need to know if using aromatase inhibitors can contribute to sexual dysfunction and a higher percentage of body fat. It is the aim of this paper to answer those questions. Joel S. Finkelstein, M.
Burnett-Bowie, M. Carl Pallais, M. Yu, M. Borges, M. Jones, M. Barry, M. Wulczyn, B. Thomas, M. Leder, M. Two groups of healthy men ages were recruited and received goserelin acetate to suppress endogenous gonadal steroids. The men were randomly assigned to receive 0 g placebo , 1. Participants in group 2 also received anastrozole Arimidex, AstraZeneca at a dose of 1 mg daily to block the aromatization of testosterone to estrogen. Primary analysis focused on comparisons of the group receiving the 5-g AndroGel dose with the other dose groups, because this dose produced testosterone levels that were similar to baseline levels.
Participants were seen every 4 weeks. At each visit, fasting blood samples were obtained to measure gonadal steroid levels, and questionnaires were administered to assess physical function, health status, vitality, and sexual function. At baseline and week 16, body fat and lean mass were assessed by means of dual-energy x-ray absorptiometry DXA ; subcutaneous- and intraabdominal-fat areas and thigh-muscle area were measured by means of computed tomography CT ; and lower-extremity strength was determined by means of a leg press.
Left blue columns above are the Testosterone only group and the right red columns the Testosterone and Arimidex group. In men receiving goserelin acetate and 0 g placebo , 1. The corresponding mean estradiol levels were 3. T bars indicate standard errors. Within each cohort, bars with the same number indicate no significant difference between dose groups.
For example, the change in the percentage of body fat Panel A did not differ significantly among the groups that received 0 g, 1. P values are for the cohort—testosterone dose interaction terms in analyses of variance comparing changes in each outcome measure between cohorts 1 and 2. Sexual desire Panel A was assessed at each visit by asking participants to rate their sex drive as compared with their sex drive before the study began?
For each man, the mean value at the final visit was then subtracted from the mean value at the baseline visit. In this study, we found that the dose of testosterone required to prevent adverse changes in a variety of measures varies considerably. When aromatization was intact, fat accumulation began with mild gonadal steroid deficiency a testosterone level of approximately to ng per deciliter , whereas lean mass, thigh-muscle area, and muscle strength were preserved until gonadal steroid deficiency was more marked a testosterone level?
Sexual desire and erectile function, the two major domains of sexual function, showed distinct patterns of change as serum testosterone levels were reduced. Observational studies have shown that lean mass and strength are reduced and fat mass is increased in men with low testosterone levels. Men with hypogonadism report less sexual activity, fewer sexual thoughts, and fewer spontaneous erections than men with normal testosterone levels.
Moreover, testosterone replacement increases lean mass, decreases fat mass, and can improve sexual function in men with hypogonadism. These observations have led to the widespread belief that undesirable changes in body composition and sexual dysfunction in men with hypogonadism are due to androgen deficiency. However, because estradiol is a metabolite of testosterone, it is difficult to distinguish the effects of androgens from those of estrogens in observational studies, or even in randomized, controlled trials if aromatizable androgens are used without the administration of an aromatase inhibitor.
By administering a variety of testosterone doses with and without concomitant aromatase inhibition, we found that changes in lean mass, thigh-muscle area, and leg-press strength were attributable to changes in testosterone levels, whereas changes in fat measures were primarily related to changes in estradiol levels.
Both androgens and estrogens contributed to the maintenance of normal libido and erectile function.