Prolactin Surge Research Articles

Plasma prolactin axis shift from placental to pituitary origin in late prepartum mice.

The placenta secretes a prolactin (PRL)-like hormone PRL3B1 (placental lactogen II), a luteotropic hormone essential for maintaining pregnancy until labor in mice. A report from 1984 examined the secretion pattern of PRL3B1 in prepartum mice. In the current study, we found contradictory findings in the secretion pattern that invalidate the previous report. By measuring maternal plasma PRL3B1 and PRL every 4 hrs from gestational day 17 (G17), we newly discovered that maternal plasma PRL3B1 levels decrease rapidly in prepartum C57BL/6 mice. Interestingly, the onset of this decline coincided with the PRL surge at G18, demonstrating a plasma prolactin axis shift from placental to pituitary origin. We also found that maternal plasma progesterone regression precedes the onset of the PRL shift. The level of Prl3b1 mRNA was determined by RT-qPCR in the placenta and remained stable until parturition, implying that PRL3B1 peptide production or secretion was suppressed. We hypothesized that production of the PRL family, the 25 paralogous PRL proteins exclusively expressed in mice placenta, would decrease alongside PRL3B1 during this period. To investigate this hypothesis and to seek proteomic changes, we performed a shotgun proteome analysis of the placental tissue using data-independent acquisition mass spectrometry (DIA-MS). Up to 5,891 proteins were identified, including 17 PRL family members. Relative quantitative analysis between embryonic day 17 (E17) and E18 placentas showed no significant difference in the expression of PRL3B1 and most PRL family members except PRL7C1. These results suggest that PRL3B1 secretion from the placenta is suppressed at G18 (E18).

RFamide-related Peptide 3 Signaling via Neuropeptide FF Receptor Stimulates Prolactin Secretion in Female Rats.

The RF-amide peptides comprise a family of neuropeptides that includes the kisspeptin (Kp), the natural ligand of kisspeptin receptor (Kiss1r), and the RFamide-related peptide 3 (RFRP-3) that binds preferentially to the neuropeptide FF receptor 1 (Npffr1). Kp stimulates prolactin (PRL) secretion through the inhibition of tuberoinfundibular dopaminergic (TIDA) neurons. Because Kp also has affinity to Npffr1, we investigated the role of Npffr1 in the control of PRL secretion by Kp and RFRP-3. Intracerebroventricular (ICV) injection of Kp increased PRL and LH secretion in ovariectomized, estradiol-treated rats. The unselective Npffr1 antagonist RF9 prevented these responses, whereas the selective antagonist GJ14 altered PRL but not LH levels. The ICV injection of RFRP-3 in ovariectomized, estradiol-treated rats increased PRL secretion, which was associated with a rise in the dopaminergic activity in the median eminence, but had no effect on LH levels. The RFRP-3-induced increase in PRL secretion was prevented by GJ14. Moreover, the estradiol-induced PRL surge in female rats was blunted by GJ14, along with an amplification of the LH surge. Nevertheless, whole-cell patch clamp recordings showed no effect of RFRP-3 on the electrical activity of TIDA neurons in dopamine transporter-Cre recombinase transgenic female mice. We provide evidence that RFRP-3 binds to Npffr1 to stimulate PRL release, which plays a role in the estradiol-induced PRL surge. This effect of RFRP-3 is apparently not mediated by a reduction in the inhibitory tone of TIDA neurons but possibly involves the activation of a hypothalamic PRL-releasing factor.

Mating-induced prolactin surge is not required for subsequent neurogenesis in male mice.

Parenting involves major behavioral transitions that are supported by coordinated neuroendocrine and physiological changes to promote the onset of novel offspring-directed behaviors. In comparison to maternal care, however, the mechanisms underlying the transition to paternal care are less understood. Male laboratory mice are predominantly infanticidal as virgins but show paternal responses 2 weeks after mating. Interestingly, males show a mating-induced surge of prolactin, which we hypothesized may be involved in initiating this behavioral transition. During pregnancy, prolactin stimulates olfactory bulb neurogenesis, which is essential for maternal behavior. Mating induces olfactory bulb neurogenesis in males, but it is unknown whether this is driven by prolactin or is important for subsequent paternal care. New olfactory neurons are generated from cells in the subventricular zone (SVZ) and take about 2 weeks to migrate to the olfactory bulb, which may account for the delayed behavioral change in mated males. We investigated whether mating increases cell proliferation at the SVZ. Males were either mated, exposed to receptive female cues, or left alone (control) and injected with Bromodeoxyuridine (BrdU, a marker of cell division). Contrary to our hypothesis, we found that mating decreased cell proliferation in the caudal lateral portion of the SVZ. Next, we tested whether prolactin itself mediates cell proliferation in the SVZ and/or new cell survival in the olfactory bulb by administering bromocriptine (prolactin inhibitor), vehicle, or bromocriptine + prolactin prior to mating. While suppressing prolactin had no effect on cell proliferation in the SVZ, administering exogenous prolactin resulted in significantly higher BrdU-labeled cells in mated but not virgin male mice. No effects of prolactin were observed on new olfactory cell survival. Taken together, prolactin may have context-dependent effects on new cell division in the SVZ, while other unknown mechanisms may be driving the effects on new olfactory cell survival following mating.

Partial loss of arcuate kisspeptin neurons in female rats stimulates luteinizing hormone and decreases prolactin secretion induced by estradiol.

Kisspeptin, neurokinin, and dynorphin (KNDy) neurons in the arcuate nucleus (ARC) control luteinizing hormone (LH) and prolactin (PRL) release, although their role in conveying the effects of estradiol (E2 ) to these hormones is not well understood. We performed a longitudinal evaluation of female rats in which KNDy neurons were ablated using a neurokinin-3 receptor agonist conjugated with saporin (NK3-SAP) to investigate the impact of the reduction of KNDy neurons on the E2 regulation of gonadal and PRL axes. NK3-SAP rats, bearing a moderate loss of ARC kisspeptin-immunoreactive (-IR) neurons (50%-90%), displayed irregular estrous cycles but essentially unaltered follicular development and a normal number of corpora lutea. Rats were then ovariectomized (OVX) and treated with a positive-feedback dose of E2 (OVX + E2 ). LH and PRL were measured in the tail blood by an enzyme-linked immunosorbent assay. The E2 -induced LH surge was amplified, whereas the PRL rise was decreased in NK3-SAP rats compared to Blank-SAP control. After 10 days of no hormonal treatment, basal LH levels were equally elevated in NK3-SAP and controls. Tyrosine hydroxylase (TH) phosphorylation in the median eminence, in turn, was increased in NK3-SAP rats, with no change in the number of ARC TH-IR neurons. Thus, KNDy neurons exert concurrent and opposite roles in the E2 -induced surges of LH and PRL. The partial loss of KNDy neurons disrupts ovarian cyclicity but does not preclude ovulation, consistent with the disinhibition of the LH preovulatory surge. Conversely, KNDy neurons tonically inhibit the enzymatic activity of tuberoinfundibular dopaminergic neurons, which appears to facilitate PRL release in response to E2 .

A CASE OF RECURRENT HIVES WITH LACTATION

<h3>Introduction</h3> Development of hives due to lactation is a rare phenomenon seen in the postpartum period. Lactation is influenced by oxytocin and prolactin release, which stimulates lactogenesis, and initiates milk secretion. We describe a rare case of postpartum hives that improved with the use of bromocriptine. <h3>Case</h3> A 33-year-old female presented to clinic with recurrent hives postpartum. Three years prior to presentation she delivered her first child via scheduled cesarean section. After four days of colostrum feeding, she began breastfeeding, but developed diffuse hives within 20 minutes. Although initially resolving with diphenyhradmine, she had recurrent flare of hives every 2-3 hours, resulting in two hospitalizations and intravenous diphenhydramine for persistent hives. Her hives disappeared on postpartum day nine. She delivered her second child via caesarean section. She developed severe, diffuse hives on the fourth day of hospitalization at the time of lactogenesis, refractory to intravenous diphenhydramine, H2-antagonists and methylprednisolone. She was started on bromocriptine with improvement in her hives within hours of administration. <h3>Discussion</h3> Hives with breastfeeding represents a unique phenomenon that can be debilitating postpartum. There are few case reports detailing lactation anaphylaxis, an IgE-independent reaction related to a prolactin surge at time of let-down. Similarly, our patient presents with two recurrent episodes of hives at the time of lactation initiation. This theory is supported by her rapid improvement with administration of bromocriptine, a dopamine antagonist that suppresses prolactin secretion. Early recognition of prolactin-induced hives could allow for intervention prior to delivery with antihistamines, glucocorticoids, and bromocriptine to provide future guidance with subsequent deliveries.

Elevated prolactin secretion during proestrus in mice: Absence of a defined surge.

Throughout the reproductive cycle in rodents, prolactin levels are generally low. In some species, including rats, a prolactin surge occurs on proestrus with peak concentrations coinciding with the preovulatory luteinizing hormone (LH) surge. In mice, however, there are conflicting reports relating to the occurrence and timing of a proestrous prolactin surge. To gain further insight into the incidence and characteristics of this surge in mice, we have used serial tail tip blood sampling and trunk blood collection from both C57BL/6J (inbred) and Swiss Webster (outbred) mouse strains to build a profile of prolactin secretion during proestrus in individual mice. A clearly defined LH surge was detected in most animals, suggesting the blood sampling approach was suitable for detecting patterns of hormone secretion on proestrus. Despite this, levels of prolactin were quite variable between individuals. Overall both mouse strains showed a generalized rise in prolactin levels on the day of proestrus compared with levels seen in diestrus. This pattern is quite distinct from the discreet, circadian‐entrained surge observed in rats.

Maternal prolactin levels during late pregnancy and nurturing behavior of offspring in mice.

Elucidating the mechanisms underlying nurturing and neglect behaviors is meaningful but challenging. Recently, we found that CIN85-deficient mice had reduced pituitary hormone prolactin secretion during late pregnancy, and their pups later showed an inhibited nurturing behavior. To examine whether this phenomenon could be reproduced in normal mice and not just CIN85-deficient mice, we investigated the nurturing behavior of offspring born to mothers whose blood prolactin levels had been reduced by bromocriptine administration during late pregnancy. First, to determine when bromocriptine treatment should be started, we investigated the detailed changes in blood prolactin levels in late pregnancy in mice, resulting in the identification of the prepartum prolactin surge. Furthermore, prolactin receptors in the fetal hypothalamus were expressed to the same extent as in the adult hypothalamus. Treatment with bromocriptine decreased the plasma concentrations of prolactin to the basal range throughout late pregnancy. However, against expectations, the proportion of the resultant pups exhibiting nurturing behaviors as adults was as high as that in the mice without bromocriptine treatment. In conclusion, the elimination of prolactin secretion during late pregnancy alone does not induce neglect-like behavior in offspring, suggesting that CIN85-deficient mice appear to involve another factor due to CIN85 deficiency besides prolactin deficiency.

The role of placental iodine storage in the neonatal thyroid stimulating hormone surge: iodine as a driving force to adapt the terrestrial life.

Iodine plays a pivotal role in adaptation during the transition from intrauterine to extrauterine life. Although it is well known that the placenta plays a role in iodine storage, a relationship between the neonatal thyroid stimulating hormone (TSH) peak and placental iodine concentration has not been established. This study focuses on the role of placental iodine concentration in the TSH surge after delivery. This study included 42 mothers and their newborns, none of whom had perinatal risk factors. The following samples were collected to analyze iodine: placental tissue, amniotic fluid (AF), and 24-h maternal urine. Blood was drawn from the umbilical cord (uc), newborns (at the 1st-24th hours), and mothers (at 1st hour) to analyze the following hormones: TSH, freeT4/T3(fT4/fT3), human chorionic gonadotrophin (hCG), prolactin (PRL), follicle stimulating hormone (FSH), luteinizing hormone (LH), and cortisol. The mean iodine levels of placental tissue, AF, and 24-h maternal urine were as follows: 29.06 ± 45.88μg/kg, 182.80 ± 446.51µg/L, and 498.35 ± 708.34µg/L, respectively. The mean TSH and hCG values were 32.41 ± 13.96mIU/ml and 30.66 ± 18.55mIU/ml, respectively, at the 1st hour. Placental iodine had strong, very strong, and weak negative correlations with TSH, hCG, and PRL, respectively (rTSH = - 0.763, p < 0.001;rHCG = - 0.919, p < 0.001; rPRL = - 0.312, p = 0.044). This study showed that the placental iodine level was inversely correlated with neonatal TSH, hCG, and PRL. It indicates that placental iodine concentration is an efficient driving force shaping the dynamic pattern of the neonatal TSH peak in addition to hCG and PRL surges, which reflects the adaptive effort in the transition from intrauterine to extrauterine life.

Reduced dopaminergic tone during lactation is permissive to the hypothalamic stimulus for suckling-induced prolactin release.

Dopamine from tuberoinfundibular dopaminergic (TIDA) neurones tonically inhibits prolactin (PRL) secretion. Lactational hyperprolactinaemia is associated with a reduced activity of TIDA neurones. However, it remains controversial whether the suckling-induced PRL surge is driven by an additional decrease in dopamine release or by stimulation from a PRL-releasing factor. In the present study, we further investigated the role of dopamine in the PRL response to suckling. Non-lactating (N-Lac), lactating 4hour apart from pups (Lac), Lac with pups return and suckling (Lac+S), and post-lactating (P-Lac) rats were evaluated. PRL levels were elevated in Lac rats and increased linearly within 30 minutes of suckling in Lac+S rats. During the rise in PRL levels, dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the median eminence (ME) and neurointermediate lobe of the pituitary did not differ between Lac+S and Lac rats. However, dopamine and DOPAC were equally decreased in Lac and Lac+S compared to N-Lac and P-Lac rats. Suckling, in turn, reduced phosphorylation of tyrosine hydroxylase in the ME of Lac+S. Domperidone and bromocriptine were used to block and activate pituitary dopamine D2 receptors, respectively. Domperidone increased PRL secretion in both N-Lac and Lac rats, and suckling elicited a robust surge of PRL over the high basal levels in domperidone-treated Lac+S rats. Conversely, bromocriptine blocked the PRL response to suckling. The findings obtained in the present study provide evidence that dopamine synthesis and release are tonically reduced during lactation, whereas dopamine is still functional with respect to inhibiting PRL secretion. However, there appears to be no further reduction in dopamine release associated with the suckling-induced rise in PRL. Instead, the lower dopaminergic tone during lactation appears to be required to sensitise the pituitary to a suckling-induced PRL-releasing factor.

Prolactin and human weight disturbances: A puzzling and neglected association.

Weight gain at the outset of prolactinomas in many women is well documented. Yet, this symptom is absent from the clinical descriptions of the disease in textbooks and reviews. This omission is almost certainly due to the absence of a physiological explanation for the phenomenon, as prolactin is not a recognized fat promoting hormone. In this review we present the clinical evidence for a relationship between prolactin and fat accumulation and address some possible mechanisms involved. We put forward the hypothesis that prolactin is a component of a neuroendocrine program - maternal subroutine - aimed at optimizing the care of the young through the production of milk, promotion of maternal behavior and increase in the metabolic efficiency of the mother. These adaptations can enable her to face the extraordinary metabolic expenses of pregnancy and nursing, especially during times of suboptimal environmental conditions. We emphasize the uniqueness of prolactin in that it is a hormone that is tonically inhibited and which has its major effects on the regulation of an inter-individual (the mother - offspring dyad), rather than an intra-individual, system. This approach opens a window to consider the possibility of external events as regulators of this system. It also allows addressing a variety of hitherto unexplained findings reported in the literature. Examples include: association of prolactinomas with paternal deprivation and with stressful life events; pseudocyesis; acute life event-driven episodes of galactorrhea; episodes of rapid weight gain following a life event; prolactin surges (without associated cortisol surges) following some psychological stresses.

Impact of Triclosan on Female Reproduction through Reducing Thyroid Hormones to Suppress Hypothalamic Kisspeptin Neurons in Mice.

Triclosan (TCS), a broad-spectrum antimicrobial agent, is widely used in clinical settings and various personal care products. The aim of this study was to evaluate the influence of TCS on reproductive endocrine and function. Here, we show that the exposure of adult female mice to 10 or 100 mg/kg/day TCS caused prolongation of diestrus, and decreases in antral follicles and corpora lutea within 2 weeks. TCS mice showed decreases in the levels of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH) and progesterone, and gonadotrophin-releasing hormone (GnRH) mRNA with the lack of LH surge and elevation of prolactin (PRL). TCS mice had lower kisspeptin immunoreactivity and kiss1 mRNA in anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC). Moreover, the estrogen (E2)-enhanced AVPV-kisspeptin expression was reduced in TCS mice. In addition, the serum thyroid hormones (triiodothyronine (T3) and thyroxine (T4)) in TCS mice were reduced with increases in levels of thyroid stimulating hormone (TSH) and thyroid releasing hormone (TRH). In TCS mice, the treatment with Levothyroxine (L-T4) corrected the increases in PRL, TSH and TRH; the administration of L-T4 or type-2 dopamine receptors agonist quinpirole inhibiting PRL release could rescue the decline of kisspeptin expression in AVPV and ARC; the treatment with L-T4, quinpirole or the GPR45 agonist kisspeptin-10 recovered the levels of serum LH and FSH and progesterone, and GnRH mRNA. Furthermore, TCS mice treated with L-T4 or quinpirole resumed regular estrous cycling, follicular development and ovulation. Together, these results indicate that exposing adult female mice to TCS (≥10 mg/kg) reduces thyroid hormones causing hyperprolactinemia that then suppresses hypothalamic kisspeptin expression, leading to deficits in reproductive endocrine and function.

Coordination or Coincidence? The Relationship between Prolactin and Gonadotropin Secretion

A recent paper demonstrates that kisspeptin can stimulate the secretion of both prolactin and luteinizing hormone (LH). This provides novel insight into mechanisms that could account for previous observations of concordant patterns of secretion of the two hormones, such as pulsatile secretion with simultaneous pulses, as well as the preovulatory surges of both prolactin and LH.

Effects of photoperiod modulation and melatonin feeding around drying-off on bovine mammary gland involution

The risk for a dairy cow to acquire new intramammary infections is high during the transition from lactation to the dry period, because of udder engorgement and altered immune functions. Once the gland is fully involuted, it becomes much more resistant to intramammary infections. Therefore, strategies to depress milk yield before drying-off and accelerate the involution process after drying-off could be beneficial for udder health. The objective of this study was to assess the effect of photoperiod manipulation and melatonin feeding from 14 d before to 14 d after drying-off on the speed of the involution process. Thirty Holstein cows in late lactation were randomly allocated to one of the following treatments: (1) a long-day photoperiod (16 h of light: 8 h of darkness), (2) a short-day photoperiod (8 h of light: 16 h of darkness), and (3) a long-day photoperiod supplemented by melatonin feeding (4 mg/kg of body weight). Milk and blood samples were collected on d -26, -19, -12, -5, -1, 1, 3, 5, 7, 10, and 14 relative to the last milking to determine concentrations of mammary gland involution markers and serum prolactin. Additional blood samples were taken around milking on d -15, before the start of the treatments, and on d -1, before drying-off, to evaluate the treatment effects on milking-induced prolactin release. The short-day photoperiod slightly decreased milk production and basal prolactin secretion during the dry period. The milking-induced prolactin surge was smaller on d -1 than on d -15 regardless of the treatments. Lactoferrin concentration, somatic cell count, and BSA concentration as well as matrix metalloproteinase-2 and -9 activities increased in mammary secretions during the first 2 wk of the dry period, whereas milk citrate concentration and the citrate:lactoferrin molar ratio decreased. The rates of change of these parameters were not significantly affected by the treatments. The long-day photoperiod supplemented by melatonin feeding did not affect milk production, prolactin secretion, or mammary gland involution. Under the conditions in this study, photoperiod modulation and melatonin feeding did not appear to affect the rate of mammary gland involution.

α-Estrogen and Progesterone Receptors Modulate Kisspeptin Effects on Prolactin: Role in Estradiol-Induced Prolactin Surge in Female Rats.

Kisspeptin (Kp) regulates prolactin (PRL) in an estradiol-dependent manner. We investigated the interaction between ovarian steroid receptors and Kp in the control of PRL secretion. Intracerebroventricular injections of Kp-10 or Kp-234 were performed in ovariectomized (OVX) rats under different hormonal treatments. Kp-10 increased PRL release and decreased 3,4-dihydroxyphenylacetic acid levels in the median eminence (ME) of OVX rats treated with estradiol (OVX+E), which was prevented by tamoxifen. Whereas these effects of Kp-10 were absent in OVX rats, they were replicated in OVX rats treated with selective agonist of estrogen receptor (ER)α, propylpyrazole triol, but not of ERβ, diarylpropionitrile. Furthermore, the Kp-10-induced increase in PRL was two times higher in OVX+E rats also treated with progesterone (OVX+EP), which was associated with a reduced expression of both tyrosine hydroxylase (TH) and Ser40-phosphorylated TH in the ME. Kp-10 also reduced dopamine levels in the ME of OVX+EP rats, an effect blocked by the progesterone receptor (PR) antagonist RU486. We also determined the effect of Kp antagonism with Kp-234 on the estradiol-induced surges of PRL and luteinizing hormone (LH), using tail-tip blood sampling combined with ultrasensitive enzyme-linked immunosorbent assay. Kp-234 impaired the early phase of the PRL surge and prevented the LH surge in OVX+E rats. Thus, we provide evidence that Kp stimulation of PRL release requires ERα and is potentiated by progesterone via PR activation. Moreover, alongside its essential role in the LH surge, Kp seems to play a role in the peak phase of the estradiol-induced PRL surge.

Influence of dynorphin on estradiol- and cervical stimulation-induced prolactin surges in ovariectomized rats.

Prolactin is an anterior pituitary hormone necessary for fertility, pregnancy maintenance, lactation, and aspects of maternal behavior. In rodents, there is a surge of prolactin on the afternoon of proestrus, and a semi-circadian pattern of prolactin surges during early pregnancy, with a diurnal and nocturnal surge every day. Both of these patterns can be replicated in ovariectomized rats. A prior study demonstrated that central antagonism of κ-opioid receptors, the target of dynorphin, largely abolished the nocturnal prolactin surge in pregnant rats. We build on this to determine whether dynorphin, perhaps from the arcuate population that co-express kisspeptin, neurokinin B, and dynorphin (KNDy neurons), also contributes to the estradiol- or cervical stimulation-induced surges in ovariectomized rats. Ovariectomized rats were treated with either estradiol or cervical stimulation to induce prolactin surge(s). Blood samples were taken around the expected surge time to determine the effect of either acute κ-opioid receptor antagonism or previous chemical ablation of the KNDy population on prolactin levels. Dynorphin antagonism does significantly disrupt the nocturnal prolactin surge, but it does not contribute to the estradiol-induced surge. Chemical ablation of KNDy neurons had opposite effects; ablation of 40% of the KNDy neurons had no impact on the nocturnal prolactin surge, while a somewhat larger ablation significantly reduced the size of the estradiol-induced surge. We conclude that dynorphin is likely a controlling factor for the nocturnal surge induced by cervical stimulation, and that other KNDy neuron products must play a role in the estradiol-induced surge.

Multiple Orgasms in Men-What We Know So Far.

There is much popular discussion on strategies to facilitate multiple orgasms in men (ie, 100,000+ hits in Google), yet the topic has not received an objective comprehensive review in the literature. To review the literature on male multiple orgasms. We searched the literature for publications on "male multiple orgasms" and factors influencing male multiple orgasms in Google, PubMed, and PsychINFO. This yielded 15 relevant publications. A comprehensive overview on the topic of male multiple orgasms and factors that influence the propensity of men to experience multiple orgasms. Few men are multiorgasmic: <10% for those in their 20s, and <7% after the age of 30. The literature suggests 2 types of male multiple orgasms: "sporadic" multiorgasms, with interorgasmic intervals of several minutes, and "condensed" multiorgasms, with bursts of 2-4 orgasms within a few seconds to 2 minutes. Multiple orgasms appear physiologically similar to the single orgasm in mono-orgasmic men. However, in a single case study, a multiorgasmic man did not experience with his first orgasm the prolactin surge that usually occurs with orgasm in mono-orgasmic men. Various factors may facilitate multiple orgasms: (1) practicing to have an orgasm without ejaculation; (2) using psychostimulant drugs; (3) having multiple and/or novel sexual partners; or (4) using sex toys to enhance tactile stimulation. However, confirmatory physiological data on any of these factors are few. In some cases, the ability to experience multiple orgasms may increase after medical procedures that reduce ejaculation (eg, prostatectomy or castration), but what factor(s) influence this phenomenon is poorly investigated. Despite popular interest, the topic of male multiple orgasms has received surprisingly little scientific assessment. The role of ejaculation and physiological change during the refractory period in inhibiting multiple orgasms has barely been investigated.

Hypothalamic Effects of Tamoxifen on Oestrogen Regulation of Luteinising Hormone and Prolactin Secretion in Female Rats.

Oestradiol (E2) acts in the hypothalamus to regulate luteinising hormone (LH) and prolactin (PRL) secretion. Tamoxifen (TX) has been extensively used as a selective oestrogen receptor modulator, although its neuroendocrine effects remain poorly understood. In the present study, we investigated the hypothalamic effects of TX in rats under low or high circulating E2 levels. Ovariectomised (OVX) rats treated with oil, E2 or TX, or E2 plus TX, were evaluated for hormonal secretion and immunohistochemical analyses in hypothalamic areas. Both E2 and TX reduced LH levels, whereas TX blocked the E2 -induced surges of LH and PRL. TX prevented the E2 -induced expression of progesterone receptor (PR) in the anteroventral periventricular nucleus (AVPV) and arcuate nucleus (ARC), although it did not alter PR expression in OVX rats. TX blocked the E2 induction of c-Fos in AVPV neurones, consistent with the suppression of LH surge. However, TX failed to prevent E2 inhibition of kisspeptin expression in the ARC. In association with the blockade of PRL surge, TX increased the phosphorylation of tyrosine hydroxylase (TH) in the median eminence of OVX, E2 -treated rats. TX also precluded the E2 -induced increase in TH expression in the ARC. In all immunohistochemical analyses, TX treatment in OVX rats caused no measurable effect on the hypothalamus. Thus, TX is able to prevent the positive- but not negative-feedback effect of E2 on the hypothalamus. TX also blocks the effects of E2 on tuberoinfundibular dopaminergic neurones and PRL secretion. These findings further characterise the anti-oestrogenic actions of TX in the hypothalamus and provide new information on the oestrogenic regulation of LH and PRL.

Evidence for a Role of Prolactin in Mediating Effects of Photoperiod during the Dry Period.

Photoperiod manipulation during the lactation cycle alters milk yield, with long days (LDPP) increasing yield in lactation and short days (SDPP) in the dry period improving subsequent yield. Circulating prolactin (PRL) is directly related to day length, with LDPP increasing and SDPP decreasing PRL, respectively. Two blocks of 24 multiparous Holstein cows were used during two consecutive years to test the hypothesis that the mammary response to SDPP is the result of decreased concentrations of PRL in the circulation relative to LDPP. Cows were randomly assigned to one of three treatment groups during the dry period: SDPP, LDPP, or SDPP+PRL. Cows were returned to ambient photoperiod at calving and milk yield and DMI recorded for 120 d and 42 d, respectively. Mammary biopsies were obtained to determine rates of [3H]-thymidine incorporation into DNA in vitro. Treatment of SDPP cows with PRL caused a rapid increase in systemic PRL that reached concentrations similar to cows under LDPP. The periparturient PRL surge was similar for LDPP and SDPP+PRL cows, but those groups had greater surge concentrations versus SDPP. Cows exposed to SDPP produced more milk than LDPP cows, and there was a trend for SDPP+PRL cows to produce more milk than LDPP cows. Milk production was inversely related to the periparturient PRL surge. There was a trend for a treatment effect on mammary cell proliferation with greater proliferation in mammary tissue of SDPP cows relative to LDPP or SDPP+PRL on day −20 relative to parturition. Replacement of PRL to cows on SDPP when dry resulted in milk yield intermediate to cows on SDPP or LDPP, supporting the concept of a link between dry period PRL and yield.

Hypothalamic Prolactin Regulation of Luteinizing Hormone Secretion in the Female Rat.

Prolactin (PRL) levels increase in response to long-term antipsychotic treatment that disrupts reproductive function. Recent evidence suggests that activation of central PRL receptors (PRLR) inhibits LH secretion and in ovariectomized rats. However, the mechanisms involved, the mode of LH secretion affected and relevance to hyperprolactinemia remain unknown. We therefore investigated the contribution of central PRL/PRLR signaling to the control of estradiol-induced surges of LH and PRL and pulsatile LH secretion under basal and hyperprolactinemic conditions. First, by subjecting ovariectomized estradiol-primed rats intracerebroventricularly administered with PRL to frequent blood sampling, we demonstrated that acute activation of hypothalamic PRLR disrupts pulsatile LH secretion. Pretreatment (intracerebroventricularly) with the pure PRLR antagonist, Δ1-9-G129R-hPRL, or the γ-aminobutyric acid receptor type A antagonist, bicuculline, blocked this effect. Next, we revealed that sustained blockade of hypothalamic PRLR using Δ1-9-G129R-hPRL augmented the magnitude of LH surges induced by estradiol benzoate and progesterone treatment and suppressed the concomitant surges of PRL. Finally, we determined that acute antagonism of central PRLR is insufficient to normalize the duration of the LH pulse interval prolonged as a result of hyperprolactinemia induced by chronic exposure to the atypical antipsychotic sulpiride. These data serve as the first evidence to suggest that PRL signaling through hypothalamic PRLR inhibits pulsatile secretion of LH in a γ-aminobutyric acid receptor type A-dependent fashion and tonically restrains the magnitude of the LH surge. Furthermore, our results indicate that transient blockade of hypothalamic PRL/PRLR signaling is not an effective strategy for restoring LH pulsatility perturbed by chronic hyperprolactinemia.

Kisspeptin mediation of estradiol-induced secretion of luteinizing hormone and prolactin

In females, ovulation is coordinated by a complex set of interactions between the hypothalamus, the anterior pituitary and the gonads. Luteinizing hormone (LH) and prolactin (PRL) are pituitary hormones that have complementary roles in reproduction. There is a surge of both hormones prior to ovulation that is essential for adequate reproduction and can be mimicked by estradiol (E2) treatment in ovariectomized (OVX) rats [1], [2]. Both the preovulatory and the E2-induced LH and PRL surges in OVX rats occur at the same time of the day, indicating that circadian signals originating in the suprachiasmatic nucleus (SCN) must provide input to coordinate both LH and PRL secretion, and that response to this input depends on the steroid milieu. Kisspeptin (KISS) is the most potent stimulator of LH release and it has been recently demonstrated to also stimulate PRL release. There are two KISS neuronal populations in the rodent brain, located in the anteroventral periventricular nucleus (AVPV) and the arcuate nucleus (ARC). The ARC population coexpress kisspeptin, neurokinin B and dynorphin and are called KNDy neurons. We have developed a reduced model for kisspeptin control of PRL and LH secretion in animals without (OVX) and with E2 treatment (OVXE), based on experimental data and literature describing the roles of the two kisspeptin subpopulations (KNDy and AVPV) in PRL and LH secretion (Fig ​(Fig1A).1A). Without E2, secretion of PRL and LH remains constant. Dopamine (DA) is released from E2 inhibition and tonically inhibits PRL secretion [3]. The absence of E2 inhibition to KNDy neurons stimulates a tonic increase of LH secretion, while the AVPV subpopulation has a low level of activity, thus preventing an LH surge (Fig ​(Fig1B,1B, left). In the OVXE model, E2 directly induces a PRL surge by increasing the activity of lactotrophs and indirectly inhibiting DA neurons (Fig ​(Fig1B,1B, right). The time-of-day-signal is provided by a brief E2-dependent stimulation from neurons in the SCN. E2 inhibition of KNDy neurons decreases LH basal secretion while stimulation of the AVPV by E2, together with the circadian SCN signal, produces the LH surge (Fig ​(Fig1B,1B, right). The modeling simulation predicts that the two KISS subpopulations have dramatically different effects on the LH surge: ablation of AVPV eliminates the surge without changing basal LH levels, while ablation of KNDY neurons would reduce basal levels and have a modest effect on the LH surge. KNDy ablation would also reduce the PRL surge. Figure 1 A mathematical model reproducing the surges of LH and PRL. (A) Model diagram which was implemented in a system of differential equations. (B) Results of modeling simulations for OVX (left) and OVXE (right). Levels of hormones and neurotransmitters (in ...