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Circulating Prolactin Levels and Risk of Epithelial Ovarian Cancer
Abstract
Purpose:
Indirect evidence from experimental and epidemiological studies suggests that prolactin may be involved in ovarian cancer development. However, the relationship between circulating prolactin levels and risk of ovarian cancer is unknown.
Methods:
We conducted a nested case-control study of 230 cases and 432 individually matched controls within three prospective cohorts to evaluate whether pre-diagnostic circulating prolactin is associated with subsequent risk of ovarian cancer. We also assessed whether lifestyle and reproductive factors are associated with circulating prolactin among controls.
Results:
Prolactin levels were significantly lower among post- versus pre-menopausal women, parous versus nulliparous women, and past versus never users of oral contraceptives in our cross-sectional analysis of controls. In our nested case-control study, we observed a non-significant positive association between circulating prolactin and ovarian cancer risk (OR(Q4vsQ1) 1.56, 95 % CI 0.94, 2.63, p trend 0.15). Our findings were similar in multivariate-adjusted models and in the subgroup of women who donated blood ≥5 years prior to diagnosis. We observed a significant positive association between prolactin and risk for the subgroup of women with BMI ≥25 kg/m(2) (OR(Q4vsQ1) 3.10, 95 % CI 1.39, 6.90), but not for women with BMI <25 kg/m(2) (OR(Q4vsQ1) 0.81, 95 % CI 0.40, 1.64).
Conclusions:
Our findings suggest that prolactin may be associated with increased risk of ovarian cancer, particularly in overweight/obese women. Factors associated with reduced risk of ovarian cancer, such as parity and use of oral contraceptives, were associated with lower prolactin levels, which suggests that modulation of prolactin may be a mechanism underlying their association with risk.
... A total of 24 records were identified from the primary searches; ten full reports were included in this review after full-text assessment 3,8,9,11,13,16,18,31,35,37 . Seven of the ten comprised studies that investigated the association between oral ...
... Five of the ten studies were cohort studies (Appendix C), five were case-control studies or derivatives of case-control studies (Appendix D). Three out of the seven studies examining the association between oral contraceptive use and epithelial ovarian cancer analyzed odds ratio as the outcome measure 8,9,11 ; two analyzed hazards ratio as the outcome measure 3,35 ; one measured mortality risks 18 ; and one measured relative risk 12 . ...
... Five out of the seven studies reported in Appendix A concluded a protective effect between oral contraceptive use and the development of ovarian cancer -three reported an association between OC use and lowered risk in ovarian cancer development 9,11,35 ; two reported an association between OC use and improved cervical cancer survival outcomes 13,18 . ...
Epithelial ovarian cancer, the most lethal of the gynecological cancers, is typically diagnosed at advanced stages. Women diagnosed with advance-staged (i.e., stage III and IV according to the International Federation of Gynecology and Obstetrics) epithelial ovarian cancer are more likely to have recurrent episodes within 18 months17. According to a 2012 2016 case analysis conducted by the surveillance, epidemiology, and end results, or SEER program, the incidence of ovarian cancer was 11.4 per 100,000 women in all races per year with the highest incidence in non-Hispanic whites, of 11.9 per 100,000 women and the lowest incidence in Asians / Pacific Islanders women, of 9.4 per 100,000 persons per year. The mortality incidence was 7.0 per 100,000 persons in all races per year in the United States. Many cancers originate from genetic mutations, including ovarian cancer. Studies indicate epithelial ovarian tumors develop in two distinctive pathways with type I arising from ovarian epithelium and inclusion germ cell layers and type II deriving from fallopian tubular epithelial origins. The mutation product of p53 results in various clinical symptoms and end points. Clinicians also have recognized the association of BRCA1 and BRCA2 genes with both of ovarian cancer and breast cancer2. A multivariate analysis conducted by Gallagher et al.14 revealed that multiple organ systems are prone to be involved during an ovarian malignancy, because there is a lack of distinct symptomatology, which allows the cancer to spread prior to detection. 2 Numerous studies also have indicated assorted risk factors contribute to the incidence and survival rate identifying racial/ethnical differences, genetic risk factors as the BRCA genes, and nongenetic risk factors including reproductive and hormonal factors, environmental and lifestyle factors. The racial differences in incidence and survival rates within the United States resemble the global pattern, with the highest incidence and mortality rates among non-Hispanic whites, followed by Hispanics, and the lowest incidence and mortality rates are among non-Hispanic blacks and Asians. The exact causes of racial disparities of epithelial ovarian cancer is still left unclear, the reasons are likely to be diverse. Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) both stimulate the ovaries to produce steroids in females. Simon et al (1983) concluded, based on in vitro studies, that these hormones contribute to the malignant epithelial tumors. Aside from the oral contraceptive use research conducted by CDC32, several hormonal factors also have been associated with the development of epithelial ovarian cancer. Studies have suggested an association between lower parity and an increased risk of developing aggressive epithelial ovarian cancer6,23. Women with longer ovulatory history are exposed to a greater risk of advanced epithelial ovarian cancer as well23. Women who have had a hysterectomy or experienced early-age menopause are at reduced risk of epithelial ovarian cancer3. Menstrual cycle irregularity and younger age at menarche also have been associated with lower risk of deaths from high-grade epithelial ovarian cancer29. 3 From 1990s to 2000s, there had been seven new hormonal contraceptive regimens approved by the Federal Drug and Administration (FDA). The birth control shot, depot medroxyprogesterone acetate (DMPA) along with the arm implant were introduced in the 1990s. The intrauterine device (IUD) that releases levonorgestrel daily was approved in 2000. The following year, transdermal patch and vaginal ring were brought to the market. In 2003, combined oral contraceptive were introduced to the public and became common and popular7,39. All these various types of hormonal contraceptives differ in effectiveness and availability, but they all introduce hormones to regulate ovulation and inhibit body’s natural cyclic hormones to prevent pregnancy44. Decades of research suggest that there are many factors related to the prognostic characteristics of epithelial ovarian cancer; in fact, abundant sources have investigated the association of hormonal factors to epithelial ovarian cancer. Thigpen et al (1993) analyzed a pooled database from the Gynecologic Oncology Group and specified age as a determinant for pathological outcome in which women aged 69 and older had a poorer prognosis than younger women34. One of the early studies, conducted in the 1980s by the United States Centers for Disease Control and Prevention (CDC), the Cancer and Steroid Hormone Study (CASH), revealed that regular users of contraceptive pills for 10 years or more had a lower lifetime risk of epithelial ovarian cancer38. Based on such findings, a World Health Organization collaborative study further indicated that there were no remarkable differences in the level of protection based on the levels of dosage in contraceptive pills27. Furthermore, a meta-analysis conducted by Wheeler et al (2019) identified that any type of intrauterine device they investigated was associated with a lower incidence of ovarian cancer.
... Notably, prolactin levels are positively associated with breast cancer risk [6][7][8][9][10][11][12] and perhaps also ovarian cancer risk [13]. Prolactin is a hormone that may promote breast carcinogenesis by decreasing apoptosis and increasing cellular proliferation and estrogen responsiveness [10-12, 14, 15]. ...
... We combined data from the NHS2 and second blood draw within NHS to specifically evaluate associations between SSRI use and prolactin levels ( Table 3). We found no association between SSRI use and geometric mean prolactin levels (SSRI users: 13 For both AD use overall and SSRIs specifically, findings were similar when restricting to the subgroup of women without severe depressive symptoms (data not shown), though interaction with BMI category was not assessed due to small numbers. ...
Purpose
To determine whether antidepressants (AD), specifically selective serotonin reuptake inhibitors (SSRIs), are linked to elevated prolactin levels among the general population.
Methods
Circulating prolactin levels were available for 4593 healthy participants in the Nurses’ Health Study (NHS) and NHS2, including 267 AD users. We fit generalized linear models to calculate and compare adjusted mean prolactin levels between AD users and non-users and further among SSRI users. Multivariable logistic regression was used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for “elevated” prolactin levels (>11 ng/mL) comparing AD users to non-users. We evaluated AD use and change in prolactin levels among 610 NHS participants with two measurements an average of 11 years apart.
Results
Adjusted geometric mean prolactin levels were similar among SSRI users (13.2 ng/mL, 95 % CI 12.2–14.4), users of other classes of ADs (12.7 ng/mL, 95 % CI 11.0–14.6), and non-users (13.1 ng/mL, 95 % CI 12.8–13.4). Neither AD use (OR 1.17, 95 % CI 0.89–1.53) nor SSRI use (OR 0.95, 95 % CI 0.66–1.38) was associated with elevated prolactin levels. Change in prolactin levels was similar across women who started, stopped, consistently used, or never used ADs.
Conclusions
This study does not support the hypothesis that AD use would influence breast cancer risk via altered prolactin levels. These results provide some evidence that use of ADs to treat depression or other conditions may not substantially increase prolactin levels in the majority of women.
... Доказано, что повышенный уровень ПРЛфактор риска развития рака яичников, особенно у женщин с избыточной массой тела и ожирением. Кроме того, гиперпролактинемия (ГПРЛ) может быть ассоциирована с раком молочной железы [9,10]. ...
Hyperprolactinemia (HPRL) is one of the most common neuroendocrine syndromes which can be either a manifestation of an independent disease (pituitary tumors) or a syndrome that accompanies a number of other diseases of the hypothalamic-pituitary zone, endocrine diseases, pathology of internal organs, lesions of the central nervous system, and can also be iatrogenic (drug-induced HPRL). HPRL is more common in women but can also occur in men with various reproductive and sexual health disorders. Many drugs can cause HPRL. In order to establish the frequency of occurrence of this problem in the clinical practice of an internist, an analysis of the literature was carried out. Articles related to HPRL induced by specific types of drugs were reviewed. This review presents the current views of domestic and foreign authors on the causes and mechanisms of development of HPRL.
... Our results indicated that using OCs significantly reduced serum prolactin. Our finding agrees with Ryu et al. who found that the use of combined OCs decreased the serum prolactin level in lactating women [40], also Clendenen et al. found that parity and OCs use was associated with a decreased level of serum prolactin and ovarian cancer risk [41]. Testa et al. reported that using combined OCs insignificantly decreased serum prolactin [42]. ...
Background
Women are more affected by rheumatoid arthritis (RA) than men and the incidence of RA in women increases around the age of menopause indicating that hormonal factors may have a role in disease pathogenesis and progression. Despite several studies on the role of sex hormones and oral contraceptives (OCs) in RA patients, the effect of combined oral contraceptives on RA disease activity is still controversial, and since few studies have been performed in Egypt on this issue so we aimed to study the effect of OCs, breastfeeding, and prolactin on disease activity and their relation to the titer of autoantibodies in female Egyptian RA patients.
Results
One hundred twenty married female RA patients were classified into three groups based on the OCs use ( n = 40 each); current, past and non-users and according to lactation into three groups; lactating using OCs ( n = 22), lactating not using OCs ( n = 30), and non-lactating ( n = 68). Our patients were using combined estrogen-progestin oral contraceptives. Clinical manifestations, disease activity, and laboratory findings were determined. The clinical manifestations including arthritis, and morning stiffness were significantly reduced in current users in comparison to past and non-users. Mean DAS28 was reduced significantly ( p < 0.05) in current and past users of OCs. Also, using OCs during lactation reduced the clinical manifestations significantly. Lactating women who were not using OCs had significantly high DAS28 and ESR ( p < 0.05) in comparison to lactating using OCs and non-lactating. On the other hand, using OCs reduced serum prolactin significantly. Lactating women not using OCs had significantly high serum prolactin ( p < 0.05) and ( p < 0.001) in comparison to lactating using OCs and non-lactating respectively which was correlated with DAS28 score.
Conclusion
Oral contraceptives may be considered in RA female patients not only as a suitable birth control method but also it has a controlling effect on disease activity even during lactation.
Message
Oral contraceptives ameliorate disease activity in RA patients
... Ovarian cancer is a serious condition and patients are in high need of new treatment options. Expression of the PRLR that belongs to the cytokine receptor family is for unknown reasons high in ovarian cancer [34]. The PRLR ligand prolactin (PRL) is a hormone that exerts many functions in addition to its most established role in lactogenesis. ...
One of the potential biomarkers for ovarian cancer patients is high serum level of prolactin (PRL), which is a growth factor that may promote tumor cell growth. The prolactin receptor (PRLR) and human cytomegalovirus (HCMV) proteins are frequently detected in ovarian tumor tissue specimens, but the potential impact of HCMV infection on the PRL system have so far not been investigated. In this study, HCMV’s effects on PRL and PRLR expression were assessed in infected ovarian cancer cells (SKOV3) by PCR and Western blot techniques. The levels of both PRL and PRLR transcripts as well as the corresponding proteins were highly increased in HCMV-infected SKOV3 cells. Tissue specimens obtained from 10 patients with ovarian cancer demonstrated high expression of PRLR, HCMV-IE, and pp65 proteins. Extensive expression of PRLR was detected in all examined ovarian tumor tissue specimens except for one from a patient who had focal expression of PRLR and this patient was HCMV-negative in her tumor. In conclusion, PRL and PRLR were induced to high levels in HCMV-infected ovarian cancer cells and PRLR expression was extensively detected in HCMV-infected ovarian tissue specimens. Highly induced PRL and PRLR by HCMV infection may be of relevance for the oncomodulatory role of this virus in ovarian cancer.
... An association with PRL levels and breast [156][157][158], ovarian [159], colon [160,161] and hepatocellular [162] cancer has been suggested. Although basic science studies have implicated a role for PRL and its receptor in the pathogenesis of different malignancies [157,158,[163][164][165][166], a clear causal relationship between PRL and cancer remains controversial [158]. ...
Hyperprolactinaemia is one of the most common problems in clinical endocrinology. It relates with various aetiologies (physiological, pharmacological, pathological), the clarification of which requires careful history taking and clinical assessment. Analytical issues (presence of macroprolactin or of the hook effect) need to be taken into account when interpreting the prolactin values. Medications and sellar/parasellar masses (prolactin secreting or acting through "stalk effect") are the most common causes of pathological hyperprolactinaemia. Hypogonadism and galactorrhoea are well-recognized manifestations of prolactin excess, although its implications on bone health, metabolism and immune system are also expanding. Treatment mainly aims at restoration and maintenance of normal gonadal function/fertility, and prevention of osteoporosis; further specific management strategies depend on the underlying cause. In this review, we provide an update on the diagnostic and management approaches for the patient with hyperprolactinaemia and on the current data looking at the impact of high prolactin on metabolism, cardiovascular and immune systems.
... The first pregnancy is associated with longterm permanent alterations in hormone regulation, including circulating lower prolactin levels; 18,19 higher circulating prolactin has been associated with ovarian cancer risk. 20 This may impact etiology of all tumor types similarly. In contrast, more recent pregnancy may lead to a clearance of premalignant or malignant cells (i.e., a "wash out" effect). ...
Ovarian cancer risk factors differ by histotype; however, within subtype there is substantial variability in outcomes. We hypothesized that risk factor profiles may influence tumor aggressiveness, defined by time between diagnosis and death, independent of histology. Among 1.3 million women from 21 prospective cohorts, 4,584 invasive epithelial ovarian cancers were identified and classified as highly aggressive (death in <1 year, n=864), very aggressive (death in 1‐<3 years, n=1,390), moderately aggressive (death in 3‐<5 years, n=639), and less aggressive (lived 5+ years, n=1,691). Using competing risks Cox proportional hazards regression, we assessed heterogeneity of associations by tumor aggressiveness for all cases and among serous and endometrioid/clear cell tumors. Associations between parity (phet=0.01), family history of ovarian cancer (phet=0.02), body mass index (BMI; phet≤0.04) and smoking (phet<0.01) and ovarian cancer risk differed by aggressiveness. A first/single pregnancy, relative to nulliparity, was inversely associated with highly aggressive disease (HR: 0.72; 95% CI [0.58‐0.88]), no association was observed for subsequent pregnancies (per pregnancy, 0.97 [0.92‐1.02]). In contrast, first and subsequent pregnancies were similarly associated with less aggressive disease (0.87 for both). Family history of ovarian cancer was only associated with risk of less aggressive disease (1.94 [1.47‐2.55]). High BMI (≥35 vs. 20‐<25 kg/m², 1.93 [1.46‐2.56] and current smoking (vs. never, 1.30 [1.07‐1.57]) were associated with increased risk of highly aggressive disease. Results were similar within histotypes. Ovarian cancer risk factors may be directly associated with subtypes defined by tumor aggressiveness, rather than through differential effects on histology. Studies to assess biological pathways are warranted.
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... Although no association was found between plasma PRL levels and BRCA carrier status among high-risk women, the presence of a giant prolactinoma associated with marked hyperprolactinemia in this patient could lead to an additional risk for the development of breast cancer. On the other hand, higher levels of PRL might also be associated with an increased risk of ovarian cancer [21]. ...
Background
Giant prolactinomas are very rare pituitary tumors that may exhibit an aggressive behavior and present with a life-threatening condition.
Case presentation
A 25-year-old white woman was admitted to our hospital with a headache, psychomotor retardation, reduced vision, and loss of autonomy in daily activities. Her past medical history was significant for having oligomenorrhea and a depressive syndrome since her mother’s death. She also had a breast cancer gene 1 (BRCA1) mutation and a family history of breast cancer. She had marked hyperprolactinemia (7615 ng/dL), central hypocortisolism, growth hormone deficiency, and a giant pituitary tumor (52 × 30 × 33 mm) which was shown in magnetic resonance imaging with obstructive hydrocephalus, requiring emergency surgery. Treatment with cabergoline led to a 99.8% reduction in serum prolactin levels and significant tumor shrinkage. Her depressive symptoms progressively improved and psychiatric drugs were withdrawn after 3 months of cabergoline treatment. Currently, she is being followed in Endocrinology, Neurosurgery, and Neurophthalmology out-patient clinics and in a breast cancer unit. Careful monitoring, support, and follow-up will be essential throughout this patient’s life.
Conclusions
This case is a rare presentation of a giant prolactinoma in a young woman, who presented a life-threatening event. She also had an unexpected association between diseases or symptoms that may have contributed to the delay in diagnosis. Given the concomitant presence of a giant prolactinoma, a BRCA1 mutation, and depressive symptoms, a possible association was hypothesized. The breast cancer risk in a BRCA1 mutation carrier and the possible interference of hyperprolactinemia and life events were also discussed. However this hypothesis requires further investigation.
... There is some evidence that lower levels of leptin [44] and higher levels of prolactin [45] might be associated with increased risk of ovarian cancer. ...
Background
Screening for ovarian cancer (OC) in women at high risk consists of a combination of carbohydrate antigen 125 (CA125) and transvaginal ultrasound, despite their low sensitivity and specificity. This could be improved by the combination of several biomarkers, which has been shown in average risk patients but has not been investigated until now in female BRCA mutation carriers.
Methods
Using a multiplex, bead-based, immunoassay system, we analyzed the concentrations of leptin, prolactin, osteopontin, insulin-like growth factor II, macrophage inhibitory factor, CA125 and human epididymis antigen 4 in 26 healthy wild type women, 26 healthy BRCA1 mutation carriers, 28 wildtype OC patients and 26 OC patients with BRCA1 mutation.
Results
Using the ROC analysis, we found a high overall sensitivity of 94.3% in differentiating healthy controls from OC patients with comparable results in the wildtype subgroup (sensitivity 92.8%, AUC = 0.988; p = 5.2e-14) as well as in BRCA1 mutation carriers (sensitivity 95.2%, AUC = 0.978; p = 1.7e-15) at an overall specificity of 92.3%.
The used algorithm also allowed to identify healthy BRCA1 mutation carriers when compared to healthy wildtype women (sensitivity 88.4%, specificity 80.7%, AUC = 0.895; p = 6e-08), while this was less pronounced in patients with OC (sensitivity 66.7%, specificity 67.8%, AUC = 0.724; p = 0.00065).
Conclusion
We have developed an algorithm, which can differentiate between healthy women and OC patients and have for the first time shown, that such an algorithm can also be used in BRCA mutation carriers. To clarify a suggested benefit to the existing early detection program, large prospective trials with mainly early stage OC cases are warranted.
... The association of PRL and its receptor with tumor progression was first established on animal models many decades ago [5]. Recently, there are several studies that involve PRL in the development of different types of cancer such as breast [6][7][8], prostate [9,10], ovarian [11] and cervical [12,13]. ...
Background:
Prolactin (PRL) has been implicated in the development of different types of cancer. However, signaling pathways might be activated depending on various forms of prolactin receptor (PRLR). JAK/STAT is an important pathway associated with PRL effects. The activation of JAK/STAT pathway might activate antiapoptotic genes that could importantly lead to progression of tumorigenesis. Recently, we have reported that PRL is associated with cell survival by inhibition of apoptosis and the precise activated signaling pathways for this process are still questioned. The purpose of this study was to evaluate the activation of different signaling pathways in response to PRL as well as to identify the induction of antiapoptotic genes.
Methods:
Cervical cancer cell lines HeLa, SiHa and C-33 A were stimulated with PRL (200 ng/mL) for 30 and 60 min and non stimulated cells were used to measure basal protein expression. Inhibition assays were performed by using Jak2 specific inhibitor AG490, either alone or in combination with PRL for 48 h. Western blot were carried out to evaluate protein induction of the different signaling pathways and antiapoptotic proteins. Significant effects were determined by using ANOVA test.
Results:
STAT3 was significantly activated in cervical cancer lines in comparison with non-tumorigenic keratinocytes HaCaT. No significant differences were found when analyzing MAPK and PI3K signaling pathways. An increase of antiapoptotic genes Bcl-xl, Bcl-2, survivin and Mcl-1 was observed after stimulus with PRL; however, after inhibition with AG490, the induction of antiapoptotic genes was decreased.
Conclusion:
Our data suggests that STAT3 is an important signaling pathway activated by PRL in cervical cancer cells and it modulates the induction of antiapoptotic genes. Blocking STAT3 could represent a possible therapeutic strategy in cervical cancer.
... Breastfeeding elevates levels of prolactin which similarly inhibits the pulsatile secretion of gonadotropin-releasing hormones (and hence gonadotropins), resulting in anovulation. However, a recent study found that circulating prolactin levels may be associated with higher risk of ovarian cancer [36]. The data from this study did not suggest any strong association between breastfeeding and ovarian cancer risk. ...
The aim of this study was to assess associations of breastfeeding, adiposity and reproductive risk factors with ovarian cancer risk in a Singaporean population. In addition to the main analysis, interaction effects of parity on other risk factors were examined.
A retrospective cohort consisting of 28,201 women with 107 incident ovarian cancers in up to 17 years of follow-up from the Singapore Breast Cancer Screening Project (1994-1997) was studied. Hazard ratios (HRs) for risk factors were estimated using Cox proportional hazards models.
Body mass index and breastfeeding were found to have no statistical significant association with ovarian cancer risk. Gravidity was inversely associated with ovarian cancer risk [each pregnancy, adjusted HR 0.89, 95 % confidence interval (CI) 0.81, 0.97], while results for parity were very similar (per delivery, HR 0.89, 95 % CI 0.81, 0.98). Each additional year of ovulatory period was found to increase ovarian cancer risk by 2 % (HR 1.02, 95 % CI 1.00, 1.04). Each year increase in total duration of oral contraceptive use reduced ovarian cancer risk by 6 % (HR 0.94, 95 % CI 0.85, 1.02).
Parity, gravidity and shorter ovulatory period were associated with lower ovarian cancer risk. Breastfeeding and body mass index were not associated with ovarian cancer risk, while increased duration of oral contraceptive use resulted in borderline risk reduction. No significant evidence was found to suggest that parity had an interaction effect on any risk factor.
... PRL acts as a mitogen by promoting cell proliferation, inhibiting apoptosis and inducing chemoattraction in breast cancer cells (5,10,11). Blood PRL levels were found elevated in patients with hepatocellular carcinoma (12,13) and ovarian cancer (14). Cultured, immortalized ovarian epithelial cells and endometrial cells treated with exogenous PRL demonstrated increased proliferation and inhibition of chemotherapy-induced cell death (15). ...
Prolactin (PRL) is a secretory cytokine, produced by various tissues. Binding to the cognate prolactin-receptor (PRLR), it activates intracellular signaling via Jak, ERK and STAT proteins. PRL regulates diverse activities under normal and abnormal conditions, including malignancies. Previous clinical data suggest serum PRL levels are elevated in colorectal cancer patients. In this study, we first determined the expression of PRL and PRLR in colon cancer tissue and cell lines. Higher levels of PRLR expression were observed in the cancers and cell lines compared to normal colonic epithelial cells. Incubation of colon cancer cells with PRL induced JAK2, STAT3, and ERK1/2 phosphorylation and increased expression of Jagged 1 (JAG1), a Notch-1 receptor ligand. Notch signaling regulates CRC stem cell population. We observed increased accumulation of the cleaved/ active form of Notch-1 receptor (NICD), increased expression of Notch responsive genes HEY1, HES1 and stem cell marker genes DCLK1, LGR5, ALDH1 and CD44. Finally, pharmacologically inhibiting the PRL induced JAK2-STAT3 and JAK2-ERK1/2 signaling abrogated Notch activation, suggesting a role for this pathway in regulating colorectal cancer stem cells. Together, our results demonstrate that cytokine signaling induced by PRL is active in colorectal cancers and may provide a new target for therapeutic targeting.
The whole picture of psychotropics for bipolar depression (BPD) remains unclear. This review compares the differences in efficacy and safety profiles among common psychotropics for BPD. MEDLINE, EMBASE, and PsycINFO were searched for proper studies. The changes in the depressive rating scale, remission/response rates, nervous system adverse events (NSAEs), gastrointestinal adverse events (GIAEs), metabolic parameters, and prolactin were compared between medication and placebo or among medications with the Cohen's d or number needed to treat/harm. The search provided 10 psychotropics for comparison. Atypical antipsychotics (AAPs) were superior to lithium and lamotrigine at alleviating acute depressive symptoms. Lithium was more likely to induce dry mouth and nausea. Cariprazine and aripiprazole seemed to be associated with an increased risk of akathisia and upper GIAEs. Lurasidone was associated with an increased risk of developing akathisia and hyperprolactinemia. Olanzapine, olanzapine-fluoxetine combination (OFC), and quetiapine were associated with an increased risk of NSAEs, metabolic risk, dry mouth, and constipation. Cariprazine, lurasidone, OFC, or quetiapine was optimal monotherapy for BPD. Further studies are needed to assess the efficacy and safety of lamotrigine for treating BPD. Adverse events varied widely across different drug types due to variations in psychopharmacological mechanisms, dosages, titration, and ethnicities.
Ovarian cancer (OC) is characterized by a high morbidity and mortality, highlighting a great need for a better understanding of biological mechanisms that affect OC progression and improving its early detection methods. This study investigates effects of prolactin (PRL) on ovarian cancer cells, analyzes PRL receptors (PRLR) in tissue micro arrays and relates PRLR expression to survival of ovarian cancer. A database, composed of transcript profiles from OC, was searched for PRLR expression and results were put in relation to survival. Expression of PRLR in OC tissue sections and OC cell lines SKOV3, OV2008 and OVSAHO was assessed using immunohistochemistry, western blots and quantitative real-time PCR. The biological function of PRLR was evaluated by proliferation, colony formation and wound healing assays. Levels of PRLR mRNA are related to survival; in epithelial OC a high PRLR mRNA expression is related to a shorter survival. Analysis of a tissue micro array consisting of 84 OC showed that 72% were positive for PRLR immuno-staining. PRLR staining tended to be higher in OC of high grade tumors compared to lower grades. PRLR mRNA and protein can further be detected in OC cell lines. Moreover, in vitro treatment with PRL significantly activated the JAK/STAT pathway. PRLR expression is associated with OC survivals. PRL and its receptor may play an onco-modulatory role and promote tumor aggressiveness in OC. Alternatively, increased PRLR levels may form a base for the development of PRLR antagonist or PRLR antagonist-drug conjugate to increase selective uptake of anti-cancer drugs.
Background:
Prolactin is synthesized in the ovaries and may play a role in ovarian cancer etiology. One prior prospective study observed a suggestive positive association between prolactin levels and risk of ovarian cancer.
Methods:
We conducted a pooled case-control study of 703 cases and 864 matched controls nested within five prospective cohorts. We used unconditional logistic regression to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for the association between prolactin and ovarian cancer risk. We examined heterogeneity by menopausal status at blood collection, body mass index (BMI), age, and histotype.
Results:
Among women with known menopausal status, we observed a positive trend in the association between prolactin and ovarian cancer risk (ptrend=0.045; OR, quartile 4 vs. 1=1.34; 95% CI=0.97-1.85), but no significant association was observed for premenopausal or postmenopausal women individually (corresponding OR=1.38; 95%CI=0.74-2.58; ptrend=0.32 and OR=1.41; 95% CI=0.93-2.13; ptrend=0.08, respectively; pheterogeneity=0.91). In stratified analyses, we observed a positive association between prolactin and risk for women with BMI {greater than or equal to}25 kg/m2, but not BMI <25 kg/m2 (corresponding OR=2.68; 95% CI=1.56-4.59; ptrend<0.01 and OR=0.90; 95% CI=0.58-1.40; ptrend=0.98, respectively; pheterogeneity<0.01). Associations did not vary by age, postmenopausal hormone therapy use, histotype, or time between blood draw and diagnosis.
Conclusions:
We found a trend between higher prolactin levels and increased ovarian cancer risk, especially among women with a BMI >=25 kg/m2.
Impact:
This work supports a previous study linking higher prolactin with ovarian carcinogenesis in a high adiposity setting. Future work is needed to understand the mechanism underlying this association.
Objective:
BRCA mutation carriers face a high lifetime risk of developing ovarian cancer. The strong inverse association between breastfeeding and the risk of ovarian cancer is established in the general population but is less well studied among women with a germline BRCA1 or BRCA2 mutation.
Method:
Thus, we conducted a matched case-control analysis to evaluate the association between breastfeeding history and the risk of developing ovarian cancer. After matching for year of birth, country of residence, BRCA gene and personal history of breast cancer, a total of 1650 cases and 2702 controls were included in the analysis. Conditional logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (CI) associated with various breastfeeding exposures.
Results:
A history of ever-breastfeeding was associated with a 23% reduction in risk (OR = 0.77; 95%CI 0.66-0.90; P = 0.001). The protective effect increased with breastfeeding from one month to seven months after which the association was relatively stable. Compared to women who never breastfed, breastfeeding for seven or more months was associated with a 32% reduction in risk (OR = 0.68; 95%CI 0.57-0.81; P < 0.0001) and did not vary by BRCA gene or age at diagnosis. The combination of breastfeeding and oral contraceptive use was strongly protective (0.47; 95%CI 0.37-0.58; P < 0.0001).
Conclusions:
These findings support a protective effect of breastfeeding for at least seven months among women with a BRCA1 or BRCA2 mutation, that is independent of oral contraceptive use.
Ovarian cancer is the most lethal gynecologic malignancy and the fifth leading cause of cancer-related death in women. Although outcomes have improved in recent years, there remains an unmet clinical need to understand the early pathogenesis of ovarian cancer in order to identify new diagnostic approaches and agents of chemoprevention and chemotherapy. While high grade serous ovarian cancer (HGSOC), the most abundant histotype, was initially thought to arise from the ovarian surface epithelium, there is an increasing body of evidence suggesting that HGSOC originates in the fallopian tube. With this new understanding of cell of origin, understanding of disease development requires analysis with a novel perspective. Currently, factors that drive the initiation and migration of dysplastic tubal epithelial cells from the fallopian tube to the ovary are not yet fully defined. These factors include common mutations to fallopian tube epithelial cells, as well as factors originating from both the fallopian tube and ovary which are capable of inducing transformation and dissemination in said cells. Here, we review these changes, their causative agents, and various potential means of intervention.
Back ground: Cancer is the second leading cause of death throughout the world. Breast cancer, is one of the leading mortality reasons in women from Western Countries, in Iraq, breast cancer is the second reason of death After cardiovascular Diseases.
Material and method:
The study was carried out of period from October/2016-january /2017 and included (90) serum samples for Iraqi women suffered from breast cancer . Samples were divided into two groups ,the first group included (66) patients (females) their age rang (22-55) years which attended to (tumor unit) at medical city educational oncology hospital and Al-Amal Al-Waatanii hospital in Baghdad ,the second group included (38) for females apparently healthy their age (22-55) were studied as a control group. All patients women which included in this study were enrolled to a diagnostic criteria which made according to clinical, mamografical, histological finding. All of them were early diagnosed (without treatment).The disease was diagnosed by consultant medical staff at the hospital .Three (3ml) of peripheral blood has been drawn from both understudying groups, serum isolated and placed in Eppendorf tube in deep freeze (-20) until used. To determin the understudying hormones (progesterone ,prolactin and estradiol ),Eliza technique has been used while vitamin c and zinc were determined sepctrophotometricly.
Result:
By ELISA technique (ITGA2) recorded a non-significant differences in patients. Progesterone recorded a significantly increasing in patients (P
Aging intersects with reproductive senescence in women by promoting a systemic low-grade chronic inflammation that predisposes women to several diseases including ovarian cancer (OC). OC risk at menopause is significantly modified by parity records during prior fertile life. To date, the combined effects of age and parity on the systemic inflammation markers that are particularly relevant to OC initiation and progression at menopause remain largely unknown. Herein, we profiled a panel of circulating cytokines in multiparous versus virgin C57BL/6 female mice at peri-estropausal age and investigated how cytokine levels were modulated by intraperitoneal tumor induction in a syngeneic immunocompetent OC mouse model. Serum FSH, LH and TSH levels increased with age in both groups while prolactin (PRL) was lower in multiparous respect to virgin mice, a finding previously observed in parous women. Serum CCL2, IL-10, IL-5, IL-4, TNF-α, IL1-β and IL-12p70 levels increased with age irrespective of parity status, but were specifically reduced following OC tumor induction only in multiparous mice. Animals developed hemorrhagic ascites and tumor implants in the omental fat band and other intraperitoneal organs by 12 weeks after induction, with multiparous mice showing a significantly extended survival. We conclude that previous parity history counteracts aging-associated systemic inflammation possibly by reducing the immunosuppression that typically allows tumor spread. Results suggest a partial impairment of the M2 shift in tumor-associated macrophages as well as decreased stimulation of regulatory B-cells in aged mice. This long term, tumor-concurrent effect of parity on inflammation markers at menopause would be a contributing factor leading to decreased OC risk.
Prolactin (PRL) is a hormone, mainly secreted by lactotroph cells of the anterior pituitary gland. Recent studies have shown it may also be produced by many extrapituitary cells. Its well-recognized PRL plays an important role in lactation during pregnancy, but it is involved in other biological functions such as angiogenesis, immunoregulation and osmoregulation. Hyperprolactinemia is a typical condition producing reproductive dysfunction in both sexes, resulting in hypogonadism, infertility and galactorrhea. It may be also asymptomatic. Lactotroph adenomas (prolactinoma) is one of the most common cause of PRL excess, representing approximately 40% of all pituitary tumors. Several other conditions should be excluded before a clear diagnosis of hyperprolactinemia is made. Hyperprolactinemia may be secondary to pharmacological or pathological interruption of hypothalamic–pituitary dopaminergic pathways or idiopathic. Stress, renal failure or hypothyroidism are other frequent conditions to exclude in patients with hyperprolactinemia. We will review biochemical characteristics and physiological functions of that hormone. Clinical and pharmacological approach to hyperprolactinemia will also be discussed.
This overview on genetic counseling for infertile couple will describe briefly genetic basis of infertility, genetic counseling of infertility, reproductive technologies used to overcome infertility, dangers of transmitting genetic disorders to offspring, and how to prevent transmissions of genetic disorders before &/or during undergoing assisted reproduction
Colorectal cancer (CRC) is the third leading cause of cancer related deaths in the USA. Worldwide, up to 5 % of all reported cancer cases are due to CRC, with ∼60 % occurring
in industrially developed or developing countries. Environmental factors ranging from changing dietary habits to environmental toxins are associated with the development of
CRC. Germline mutations in APC, TP53, and DNA mismatch repair genes contribute to nearly 35 % of the registered CRC cases and are by far the best-studied factors for CRC. Hormones are critical regulatory factors produced by the body to regulate diverse physiological activities. Prolactin (PRL) is a polypeptide hormone, which is expressed in most mammalian species. In humans, PRL binds to PRL receptor (PRLR) and
induces the JAK-STATor JAK-STAT-ERK pathways. Studies from several groups over the last few decades have shown that PRL can regulate a spectrum of functions ranging from behavior to immune responses to tumorigenesis. Epidemiological studies related to cancer especially breast or prostrate have linked the role of PRL or receptor in the causation of tumor progression. This review sheds a brief overview about PRL or
receptor role in colorectal tumorigenesis.
Background: Prolactin is a lactogenic hormone associated with breast cancer risk in prospective studies, which used immunoassays. The immunoassay captures multiple isoforms and may not fully reflect the biologic activity of prolactin relevant to breast carcinogenesis.
Methods: We considered plasma bioactive prolactin levels measured by the Nb2 lymphoma cell bioassay, which is sensitive to the somatolactogenic activity of prolactin and growth hormone, within a nested case–control study of invasive breast cancer in the Nurses' Health Studies (NHS/NHSII). We also considered associations with breast cancer risk factors.
Results: We had bioassay measures on 1,329 cases and 1,329 controls. Bioassay levels were inversely associated with parity (4+ vs. 0 children = −18%, P = 0.01), body mass index (30+ vs. <22 kg/m2 = −16%, P < 0.01), and age at menopause (53+ vs. 48 years = −18%, P = 0.03) and positively with family history of breast cancer (yes vs. no = 14%, P < 0.01). The relative risk (RR) comparing the top versus bottom quartile of bioassay levels was 1.19 [95% confidence intervals (CI), 0.94–1.51; Ptrend = 0.18]. The association was suggestively stronger for postmenopausal (RR = 1.36; 95% CI, 0.93–1.98; Ptrend = 0.12) versus premenopausal women (RR = 0.99; 95% CI, 0.71–1.37; Ptrend = 0.71). There was an association for cases diagnosed <4 years after blood draw (RR = 2.66; 95% CI, 1.45–4.89; Ptrend < 0.01), but not for cases diagnosed later. We did not observe differential associations by estrogen receptor status or other tumor characteristics.
Conclusions: Our results show similar associations for prolactin levels measured by bioassay and by immunoassay with both breast cancer risk factors and risk.
Impact: Future work examining risk prediction model of breast cancer can use the immunoassay to accurately characterize risk. Cancer Epidemiol Biomarkers Prev; 24(1); 73–80. ©2014 AACR.
Although endogenous sex steroid hormones in premenopausal women may be associated with the risk of breast cancer and other illnesses, direct evidence to support this hypothesis is limited in large part by methodological issues in the conduct of relevant studies. One major unresolved issue is whether a single blood sample (such as is available in most epidemiological studies), collected in a specific phase of the menstrual cycle, reflects long-term levels in that phase. To address this issue, two sets of blood and urine samples were obtained from 87 premenopausal women over a 1-year period in both the follicular and luteal phases. Plasma estradiol, estrone, and estrone sulfate were measured in the blood samples obtained in both phases, whereas progesterone and urinary 2- and 16a-hydroxyestrone were measured in luteal-phase samples only. For all of the women combined, intraclass correlation coefficients (ICCs) ranged, with one exception, from 0.52 to 0.71 for the plasma estrogens and the urinary estrogen metabolites. The sole exception was for estradiol in the luteal phase (ICC = 0.19); inclusion of only women who were ovulatory in both cycles and who collected each sample 4-10 days before their next period resulted in a substantially higher ICC for estradiol in the luteal phase (ICC = 0.62; 95% confidence interval, 0.43-0.78). These data indicate that, for several plasma and urinary sex hormones, a single follicular- or luteal-phase measurement in premenopausal women is reasonably representative of hormone levels in that phase for at least a 1-year period.
Factors contributing to chronic inflammation appear to be associated with increased risk of ovarian cancer. The purpose of this study was to assess the association between circulating levels of inflammation mediators and subsequent risk of ovarian cancer.
We conducted a case-control study of 230 cases and 432 individually matched controls nested within three prospective cohorts to evaluate the association of prediagnostic circulating levels of inflammation-related biomarkers (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, TNFα, IL-1Ra, sIL-1RII, sIL-2Ra, sIL-4R, sIL-6R, sTNF-R1, and sTNF-R2) measured using Luminex xMap technology with risk of ovarian cancer.
We observed a trend across quartiles for IL-2 (OR(Q4 vs. Q1): 1.57, 95% CI: 0.98-2.52, P = 0.07), IL-4 (OR(Q4 vs. Q1): 1.50, 95% CI: 0.95-2.38, P = 0.06), IL-6 (OR(Q4 vs. Q1): 1.63, 95% CI: 1.03-2.58, P = 0.03), IL-12p40 (OR(Q4 vs. Q1): 1.60, 95% CI: 1.02-2.51, P = 0.06), and IL-13 (OR(Q4 vs. Q1): 1.42, 95% CI: 0.90-2.26, P = 0.11). Trends were also observed when cytokines were modeled on the continuous scale for IL-4 (P trend = 0.01), IL-6 (P trend = 0.01), IL-12p40 (P trend = 0.01), and IL-13 (P trend = 0.04). ORs were not materially different after excluding cases diagnosed less than 5 years after blood donation or when limited to serous tumors.
This study provides the first direct evidence that multiple inflammation markers, specifically IL-2, IL-4, IL-6, IL-12, and IL-13, may be associated with risk of epithelial ovarian cancer, and adds to the evidence that inflammation is involved in the development of this disease.
Previous prospective studies have found an association between prolactin (PRL) levels and increased risk of breast cancer. Using data from a population-based breast cancer case-control study conducted in two cities in Poland (2000-2003), we examined the association of PRL levels with breast cancer risk factors among controls and with tumour characteristics among the cases.
We analysed PRL serum levels among 773 controls without breast cancer matched on age and residence to 776 invasive breast cancer cases with available pretreatment serum. Tumours were centrally reviewed and prepared as tissue microarrays for immunohistochemical analysis. Breast cancer risk factors, assessed by interview, were related to serum PRL levels among controls using analysis of variance. Mean serum PRL levels by tumour characteristics are reported. These associations also were evaluated using polytomous logistic regression.
Prolactin levels were associated with nulliparity in premenopausal (P=0.05) but not in postmenopausal women. Associations in postmenopausal women included an inverse association with increasing body mass index (P=0.0008) and direct association with use of recent/current hormone therapy (P=0.0006). In case-only analyses, higher PRL levels were more strongly associated with lobular compared with ductal carcinoma among postmenopausal women (P=0.02). Levels were not different by tumour size, grade, node involvement or oestrogen receptor, progesterone receptor, or human epidermal growth factor receptor 2 status.
Our analysis demonstrates that PRL levels are higher among premenopausal nulliparous as compared with parous women. Among postmenopausal women, levels were higher among hormone users and lower among obese women. These results may have value in understanding the mechanisms underlying several breast cancer risk factor associations.
Prolactin (PRL) is one of the most versatile hormones in the mammalian body affecting reproductive, sexual, metabolic, immune, and other functions. It is therefore not surprising that the neural control of PRL secretion is complex, involving the coordinated actions of several hypothalamic nuclei. A plethora of experimental data exists on the hypothalamic control of hormone secretion under various physiological stimuli. There have been even mathematical models and computer studies published, which help to understand the complex hypothalamic-pituitary network. Nevertheless, the putative role of PRL for human reproduction still has to be clarified. Here, we review data on the underlying mechanisms controlling PRL secretion using both experimental and mathematical approaches. These investigations primarily focus on rhythmic secretion in rats during early pregnancy or pseudopregnancy, and they point to the important role of oxytocin as a crucial PRL-releasing factor. Recent data on human studies and their theoretical and clinical implications are reviewed as well. In particular, studies demonstrating a sustained PRL surge after sexual climax in males and females are presented, indicating possible implications for both sexual satiation and reproductive functions. Taking these data together, there is evidence for the hypothesis that the PRL surge induced by sexual activity, together with the altered PRL rhythmic pattern, is important for successful initialization of pregnancy not only in rodents but also possibly in humans. However, further investigations are needed to clarify such a role in humans.
There is increasing evidence that prolactin (PRL), a hormone/cytokine, plays a role in breast, prostate, and colorectal cancers via local production or accumulation. Elevated levels of serum PRL in ovarian and endometrial cancers have been reported, indicating a potential role for PRL in endometrial and ovarian carcinogenesis. In this study, we show that serum PRL levels are significantly elevated in women with a strong family history of ovarian cancer. We show dramatically increased expression of PRL receptor in ovarian and endometrial tumors as well as in endometrial hyperplasia, signifying the importance of PRL signaling in malignant and premalignant conditions. PRL mRNA was expressed in ovarian and endometrial tumors, indicating the presence of an autocrine loop. PRL potently induced proliferation in several ovarian and endometrial cancer cell lines. Binding of PRL to its receptor was followed by rapid phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, mitogen-activated protein kinase/ERK kinase 1, signal transducer and activator of transcription 3, CREB, ATF-2, and p53 and activation of 37 transcription factors in ovarian and endometrial carcinoma cells. PRL also activated Ras oncogene in these cells. When human immortalized normal ovarian epithelial cells were chronically exposed to PRL, a malignant transformation occurred manifested by the acquired ability of transformed cells to form clones, grow in soft agar, and form tumors in severe combined immunodeficient-beige mice. Transformation efficiency was diminished by a Ras inhibitor, providing proof that PRL-induced transformation uses the Ras pathway. In summary, we present findings that indicate an important role for PRL in ovarian and endometrial tumorigenesis. PRL may represent a risk factor for ovarian and endometrial cancers.
Surgical stress has been suggested to facilitate the growth of preexisting micrometastases as well as small residual tumor postoperatively. The purpose of this study was to examine the effects of surgical stress on ovarian cancer growth and to determine underlying mechanisms responsible for increased growth.
To mimic the effects of surgery, we did a laparotomy or mastectomy under isoflurane inhalation on athymic nude mice 4 days after i.p. tumor cell injection. Propranolol infusion via Alzet pumps was used to block the influence of sympathetic nervous system activation by surgical stress.
In both HeyA8 and SKOV3ip1 models, the mice in the laparotomy and mastectomy groups had significantly greater tumor weight (P < 0.05) and nodules (P < 0.05) compared with anesthesia only controls. There was no increase in tumor weight following surgery in the beta-adrenergic receptor-negative RMG-II model. Propranolol completely blocked the effects of surgical stress on tumor growth, indicating a critical role for beta-adrenergic receptor signaling in mediating the effects of surgical stress on tumor growth. In the HeyA8 and SKOV3ip1 models, surgery significantly increased microvessel density (CD31) and vascular endothelial growth factor expression, which were blocked by propranolol treatment.
These results indicate that surgical stress could enhance tumor growth and angiogenesis, and beta-blockade might be effective in preventing such effects.
Endogenous pituitary hormones are commonly used in clinical and epidemiologic studies and some of them are thought to influence the risk of several diseases in women. In most studies, endogenous levels of pituitary hormones are usually assessed at a single point in time, assuming that this single measurement represents the long-term biomarker status of the individual. Such an assumption is rarely tested and may not always be valid. This study examined the reproducibility of the following pituitary hormones: adrenocorticotropic hormone (ACTH), growth hormone, follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid-stimulating hormone (TSH), and prolactin, measured using the Luminex xMap method in sera of healthy premenopausal and postmenopausal women. The study included 30 premenopausal women with three yearly samples and 35 postmenopausal women with two repeated yearly samples randomly selected from an existing prospective cohort. Analysis of intraclass correlation coefficients suggested higher reproducibility in postmenopausal women compared with premenopausal women for the following hormones: FSH (0.72 and 0.37, respectively), LH (0.83 and 0.44, respectively), and growth hormone (0.60 and 0.35, respectively). The intraclass correlation coefficients were relatively high and similar between postmenopausal and premenopausal women for ACTH (0.95 and 0.94, respectively), TSH (0.85 and 0.85, respectively), and prolactin (0.72 and 0.69, respectively). This study found that serum concentrations of FSH, LH, and growth hormone are stable in postmenopausal women and that ACTH, TSH, and prolactin are stable in both premenopausal and postmenopausal women, suggesting that a single measurement may reliably categorize average levels over at least a 2-year period.
Follicular-phase (Day 11) plasma prolactin, and plasma and urinary oestrogen levels of 70 nulliparous nuns were compared with those of 80 of their sisters, of whom 62 were parous. The nuns and their nulliparous sisters did not differ significantly in their prolactin and oestrogen levels. No differences in plasma oestrogens or urinary oestriol ratio were found between the parous and the nulliparous women. However, the mean prolactin level of the nuns and their nulliparous sisters was 35% higher than that of the parous women in the sample taken approximately 1 3/4 h after rising (p less than 0.0005), and 24% higher (P less then 0.01) in the 2nd sample taken 2 h later. The elevation was independent of age, weight, and age at menarché. Age at first full-term pregnancy, at least up to the age of 30, and second or subsequent full-term pregnancies had no further effect on prolactin level. This study suggests that the effect of early first full-term pregnancy in lowering breast cancer risk may be mediated, at least in part, by permanently lowering the level of circulating prolactin.
Prolactin, a hormone indispensable for milk secretion, has been shown to enhance the development and growth of mammary tumors in rodents; however, its importance in human breast cancer is uncertain. Serum prolactin levels are known to fluctuate considerably under normal conditions, and lack of precision in the hormone measurements may have contributed to the largely negative findings in humans to date. The purpose of this study was to investigate the reliability of prolactin measurements in women using stored serum from an ongoing prospective study of breast cancer. Separate groups of postmenopausal and premenopausal women who donated multiple blood samples at approximately 1-year intervals were studied. The reliability of a single log prolactin determination, as measured by the intraclass correlation coefficient, was 0.76 for the postmenopausal women (95% confidence interval, 0.66-0.85) and 0.48 for the premenopausal women (95% confidence interval, 0.31-0.62). These findings suggest that a single measurement is sufficient to characterize the serum prolactin level of postmenopausal women for epidemiological research. For premenopausal women, however, multiple samples are desirable. Controlling for phase of the menstrual cycle does not appear to substantially improve the reliability of premenopausal measurements.
We evaluated the reproducibility of plasma hormone levels over time in 79 healthy postmenopausal women, ages 51-69 years at baseline, who were not using postmenopausal hormones. Three blood samples were collected between 1989 and 1992 from each of these women. We assessed plasma levels of estradiol, free estradiol, percentage of free estradiol, bioavailable estradiol, percentage of bioavailable estradiol, estrone, estrone sulfate, sex hormone-binding globulin (SHBG), androstenedione, testosterone, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and prolactin at each of three sample collections. The means and SD for each of the plasma estrogens, SHBG, and prolactin were similar at each collection. For the androgens, plasma levels tended to decrease over time consistent with an aging effect; decreases with increasing age were statistically significant for androstenedione, dehydroepiandrosterone, and dehydroepiandrosterone sulfate. Intraclass correlation coefficients (ICCs) ranged from 0.92 (95% confidence interval = 0.89-0.95) for SHBG to 0.53 (95% confidence interval = 0.43-0.69) for prolactin. Most correlations were at least 0.70. The ICCs did not vary by age or time since menopause. Women who changed weight over the course of the study tended to have lower ICCs for a number of the hormones, although these differences were not statistically significant. These data indicate that, for most of these plasma hormones, a single measurement can reliably categorize average levels over at least a 3-year period in postmenopausal women.
Prolactin is a protein hormone of the anterior pituitary gland that was originally named for its ability to promote lactation in response to the suckling stimulus of hungry young mammals. We now know that prolactin is not as simple as originally described. Indeed, chemically, prolactin appears in a multiplicity of posttranslational forms ranging from size variants to chemical modifications such as phosphorylation or glycosylation. It is not only synthesized in the pituitary gland, as originally described, but also within the central nervous system, the immune system, the uterus and its associated tissues of conception, and even the mammary gland itself. Moreover, its biological actions are not limited solely to reproduction because it has been shown to control a variety of behaviors and even play a role in homeostasis. Prolactin-releasing stimuli not only include the nursing stimulus, but light, audition, olfaction, and stress can serve a stimulatory role. Finally, although it is well known that dopamine of hypothalamic origin provides inhibitory control over the secretion of prolactin, other factors within the brain, pituitary gland, and peripheral organs have been shown to inhibit or stimulate prolactin secretion as well. It is the purpose of this review to provide a comprehensive survey of our current understanding of prolactin's function and its regulation and to expose some of the controversies still existing.
Early diagnosis of epithelial ovarian cancer (EOC) would significantly decrease the morbidity and mortality from this disease but is difficult in the absence of physical symptoms. Here, we report a blood test, based on the simultaneous quantization of four analytes (leptin, prolactin, osteopontin, and insulin-like growth factor-II), that can discriminate between disease-free and EOC patients, including patients diagnosed with stage I and II disease, with high efficiency (95%). Microarray analysis was used initially to determine the levels of 169 proteins in serum from 28 healthy women, 18 women newly diagnosed with EOC, and 40 women with recurrent disease. Evaluation of proteins that showed significant differences in expression between controls and cancer patients by ELISA assays yielded the four analytes. These four proteins then were evaluated in a blind cross-validation study by using an additional 106 healthy females and 100 patients with EOC (24 stage I/II and 76 stage III/IV). Upon sample decoding, the results were analyzed by using three different classification algorithms and a binary code methodology. The four-analyte test was further validated in a blind binary code study by using 40 additional serum samples from normal and EOC cancer patients. No single protein could completely distinguish the cancer group from the healthy controls. However, the combination of the four analytes exhibited the following: sensitivity 95%, positive predictive value (PPV) 95%, specificity 95%, and negative predictive value (NPV) 94%, a considerable improvement on current methodology.
• insulin-like growth factor-II
• leptin
• osteopontin
• prolactin
Throughout life, the ovarian surface epithelium (OSE) undergoes morphogenetic changes that may be hormonally regulated. To investigate this possibility, a population of cells morphologically identical to native OSE cells was isolated from estrous rabbits with collagenase, unit gravity sedimentation, and trypsin-EDTA. Cells were incubated with various concentrations of protein hormones in serum-rich medium or in a chemically defined medium containing fibronectin. Tritiated thymidine was added 24 h before interruption of cultures. Growth-promoting effects of tested hormones were more pronounced and consistent in serum-free cultures. Under these conditions, human chorionic gonadotropin (10,000 mIU/ml) caused a 2.8-fold increase in cell number and a 3.4-fold stimulation of thymidine incorporation. Luteinizing hormone (NIAMDD-oLH-24, 1.0 micrograms/ml) and follicle-stimulating hormone (NIADDK-oFSH-16, 1.0 micrograms/ml) produced, respectively, a 1.7-fold and 1.5-fold increase in cell proliferation, and over 1.4-fold and 1.3-fold stimulations of thymidine uptake. When used together, no growth stimulation by these gonadotropins was seen. Slight but significant increases in cell number (1.4-fold) and in radiolabel incorporation (1.3-fold) were observed with prolactin (NIADDK-oPrl-16, 10 ng/ml). These data indicate that some protein hormones promote the growth of OSE cells. This property may be important in regulating these cells during normal and pathologic states.
A generalized (extreme Studentized deviate) ESD many-outlier procedure is given for detecting from 1 to k outliers in a data set. This procedure has an advantage over the original ESD many-outlier procedure (Rosner 1975) in that it controls the type I error both under the hypothesis of no outliers and under the alternative hypotheses of 1, 2, …. k-l outliers. A method is given for approximating percentiles for this procedure based on the t distribution. This method is shown to be adequately accurate using Monte Carlo simulation, for detecting up to 10 outliers in samples as small as 25. Tables are given for implementing this method for n = 25(1)50(10)100(50)500; k = 10, α = .05, .Ol, .005.
The aim of this study was to clarify the significance of serum prolactin concentrations in patients with infertility and endometriosis. Forty patients with infertility and laparoscopically proven endometriosis were recruited into the study. Basal serum prolactin levels and prolactin levels after TRH administration were measured. The mean basal serum prolactin concentrations were 12.5, 16.5, 19.5, and 26.5 ng/ml and those after thyrotropin-releasing hormone (TRH) administration were 88.3, 114.2, 125.3 and 138.8 ng/ml in patients with stages I, II, III and IV endometriosis, respectively. A statistically significant relationship was found between the basal serum prolactin levels as well as those after TRH injection and the stage of the endometriosis. The patients were divided in two groups. Group I consisted of 20 patients who did not receive any treatment, while group II consisted of 20 patients who were initially treated with GnRH analogues for 24 week and subsequently with several therapeutic schemes in order to improve their fecundity. The pregnancy rate was not different between the two groups. The patients, however, who did not become pregnant had higher serum prolactin concentrations after TRH administration as compared to those who conceived. We conclude that occult hyperprolactinemia may be a cause of infertility in patients with endometriosis.
Prolactin is not commonly recognised as a hormone that changes significantly within the menstrual cycle or after menopause. The aim of this study was to determine the degree of variability of prolactin in these physiological states.
Prolactin levels obtained from 6540 subjects between January 2006 and November 2008 were divided into five groups: men, postmenopausal women and premenopausal women in follicular/non-cycling, ovulatory and luteal phases. The median and 97.5th centile was determined for each group. The 97.5th centile was used to define the upper limit of prolactin.
The prolactin median and upper limits were not significantly different in men and postmenopausal women. They were significantly higher in premenopausal women compared to men and postmenopausal women. Within premenopausal women, the prolactin median and upper limits were significantly higher in ovulatory phase compared to follicular/non-cycling and luteal phases and in luteal phase compared to follicular/non-cycling phase.
Prolactin levels varied significantly throughout the menstrual cycle, and the utility and accuracy of prolactin testing may be improved by applying specific reference intervals for each phase of the menstrual cycle. Alternatively, a single reference interval could be used if prolactin is only measured in the follicular phase, well before midcycle. Prolactin levels in postmenopausal women and men were not significantly different, and a common prolactin reference interval may be appropriate. Further studies to confirm formal reference ranges for these groups may be clinically helpful.
The prevalence of obesity, an established risk factor for many cancers, has risen steadily for the past several decades in the United States and in many parts of the world. This review synthesizes the evidence on key biological mechanisms underlying the obesity-cancer link, with particular emphasis on the impact of energy balance modulation, such as diet-induced obesity and calorie restriction, on growth factor signaling pathways and inflammatory processes. Particular attention is placed on the proinflammatory environment associated with the obese state, specifically highlighting the involvement of obesity-associated hormones/growth factors in crosstalk between macrophages, adipocytes, and epithelial cells in many cancers. Understanding the contribution of obesity to growth factor signaling and chronic inflammation provides mechanistic targets for disrupting the obesity-cancer link.
Variably-spliced prolactin receptors (PRLRs) and PRL are expressed by the ovarian cancer cell lines, TOV-112D, OV-90 and TOV-21G. Incubation in the PRLR antagonists, G129R- or S179D-PRL, or anti-PRL reduced cell number, indicating a functional autocrine PRL growth loop. Added PRL promoted, and the antagonists decreased, cell migration. When cells were stressed, added PRL decreased apoptosis and increased survival, and the antagonists had the opposite effect. Cells expressing higher long:short PRLR ratios had increased growth, survival and migration in response to PRL. Results suggest that PRLR antagonists may be therapeutically beneficial in ovarian cancer.
Pulsatile PRL secretion undergoes diurnal variation, with maximal PRL release in the evening during sleep in both women and men. However, the impact of the menopause on PRL pulsatile dynamics are largely unknown. To characterize diurnal PRL pulsatile secretion in postmenopausal women, we performed frequent venous sampling over 24 h every 10 min for serum PRL in 7 postmenopausal women (age, 56 +/- 4 yr) and in 2 control groups, 8 men (age, 25 +/- 8 yr) and 22 cycling women (age, 28 +/- 5 yr), at 3 phases of the menstrual cycle. Standard TRH tests (200 microg, i.v.) were administered at 0900 h after completion of the 24-h sampling, and PRL levels were then obtained at 0, 10, 20, 30, and 60 min in all subjects. PRL pulse characteristics were similar between the postmenopausal women and men. Mean serum PRL levels and PRL pulse frequency were significantly higher in the cycling women than in either postmenopausal women or men over 24 h and during either the day or night periods. Mean serum PRL levels and pulse frequency were significantly higher during the night compared to those during the day in all groups. Pulse amplitude was higher during the night vs. the day in all groups and was highest in the cycling women. PRL responses to TRH administration were greatest in cycling women. These data demonstrate that PRL pulse dynamics are significantly different between postmenopausal women and cycling women, and endogenous estrogen levels may have an important role in this difference. Pulsatile PRL secretion is similar between postmenopausal women and men, suggesting that estrogen levels modulate PRL dynamics across genders.
To examine the value of individual and combinations of ovarian cancer associated blood biomarkers for the discrimination between plasma of patients with type I or II ovarian cancer and disease-free volunteers.
Levels of 14 currently promising ovarian cancer-related biomarkers, including CA125, macrophage inhibitory factor-1 (MIF-1), leptin, prolactin, osteopontin (OPN), insulin-like growth factor-II (IGF-II), autoantibodies (AAbs) to eight proteins: p53, NY-ESO-1, p16, ALPP, CTSD, B23, GRP78, and SSX, were measured in the plasma of 151 ovarian cancer patients, 23 with borderline ovarian tumors, 55 with benign tumors and 75 healthy controls.
When examined individually, seven candidate biomarkers (MIF, Prolactin, CA-125, OPN, Leptin, IGF-II and p53 AAbs) had significantly different plasma levels between type II ovarian cancer patients and healthy controls. Based on the receiver operating characteristic (ROC) curves constructed and area under the curve (AUC) calculated, CA125 exhibited the greatest power to discriminate the plasma samples of type II cancer patients from normal volunteers (AUC 0.9310), followed by IGF-II (AUC 0.8514), OPN (AUC 0.7888), leptin (AUC 0.7571), prolactin (AUC 0.7247), p53 AAbs (AUC 0.7033), and MIF (AUC 0.6992). p53 AAbs levels exhibited the lowest correlation with CA125 levels among the six markers, suggesting the potential of p53 AAbs as a biomarker independent of CA125. Indeed, p53 AAbs increased the AUC of ROC curve to the greatest extent when combining CA125 with one of the other markers. At a fixed specificity of 100%, the addition of p53 AAbs to CA125 increased sensitivity from 73.8% to 85.7% to discriminate type II cancer patients from normal controls. Notably, seropositivity of p53 AAbs is comparable in type II ovarian cancer patients with negative and positive CA125, but has no value for type I ovarian cancer patients.
p53 AAbs might be a useful blood-based biomarker for the detection of type II ovarian cancer, especially when combined with CA125 levels.
Body size and reproductive factors are important risk factors of breast cancer. The aim of the present study was to examine the associations of these factors with blood concentrations of sex hormones and prolactin in premenopausal Japanese women.
We measured the plasma concentrations of estradiol, estrone, testosterone, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), follicle-stimulating hormone, luteinizing hormone, and prolactin among 436 women who had regular menstrual cycles less than 40 days long. Information on menstrual and reproductive factors including history of breastfeeding was obtained using a self-administered questionnaire. Height and weight were measured.
After controlling for age and the phase of the menstrual cycle, the body mass index (BMI) was significantly inversely associated with total estradiol, estrone and SHBG and significantly positively associated with total and free testosterone and DHEAS. Nulliparous women had significantly higher levels of total and free testosterone, DHEAS, and prolactin than parous women. Duration of breastfeeding for the first child was significantly inversely associated with free testosterone and prolactin levels.
The data suggest that an increased risk of premenopausal breast cancer associated with low BMI is partially mediated by an increased total estradiol. Androgens and prolactin may explain the breast cancer protection provided by giving birth and breastfeeding.
The plasma hormone concentrations of 30 young women, who were judged by genetic analysis to be at high risk for familial breast cancer, were compared with those of 30 matched controls identified as at low risk for the disease. The hormone measurements were obtained every second day throughout the menstrual cycle, and the results were analyzed in terms of follicular, luteal, and full-cycle mean concentrations. Comparison was carried out in a paired fashion with each high-risk and low-risk pair matched closely for height, weight, age, and reproductive history. No statistically significant differences were found in prolactin, gonadotropin, estrone, estradiol, or estriol plasma concentrations although the high-risk group displayed consistently lower values in all of the above except estriol.
Serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin, estradiol, and progesterone concentrations were measured in 58 ovulating women in different age groups (20 to 29, 34 to 39, 40 to 44, and 45 to 50 years) at five- to seven-day intervals through a single menstrual cycle and in 18 postmenopausal women sampled weekly five to six times. The over-all hormone patterns were similar in four premenopausal groups. However, mean serum FSH levels increased with age and significantly higher concentrations were found in the 40 to 50 years group than in the 20 to 29 year group. Serum LH levels did not show a similar rise with age, although follicular LH levels in the oldest group were higher than in the 20 to 29 year group. Prolactin and estradiol concentrations did not change with age prior to the menopause, but luteal progesterone levels were lower in the three older premenopausal groups than in the 20 to 29 year group. Postmenopausal women showed elevated FSH and LH, decreased prolactin, and negligible estradiol and progesterone levels. There was an over-all significant linear correlation between prolactin and estradiol concentrations. It appears that the menopause is preceded by several years of rising gonadotropin, predominantly FSH, levels. During this period, ovarian estrogen production appears to be maintained and ovulation continues, but luteal progesterone levels decline. It is likely that these premenopausal alterations in pituitary-ovarian relationships reflect depletion of ovarian follicles.
Demographic risk factors in sisters and daughters of 150 patients with breast cancer were compared to those of controls. Plasma hormone levels in 36 teen-age daughters of patients and 31 controls were also studied to ascertain whether an "abnormal" hormone pattern underlies these risk factors. The patients' sisters had, on the average, menarche four months earlier and first full-term pregnancy 12 months later than the controls. The patients' daughters did not show these differences -- apparently owing to low fertility in the patients with early menarche. The patients' daughters had higher 22d-day estradiol-plus-estrone levels than controls (24.4 vs. 19.1 ng per 100 ml, P less than 0.05). Sixth-day prolactin was also elevated (19.0 vs. 14.2 ng per 100 ml, P less than 0.05). About half the patients' daughters could clearly be distinguished from the controls' daughters by means of the sixth-day information on both estrogens and prolactin. Hypersecretion of these hormones may be important factors in breast cancer.
Although both prolactin and growth hormone are believed to play roles in the development and growth of rodent mammary cancer, the role of these hormones in human breast cancer is uncertain. Under carefully specified conditions, serum levels of these hormones were determined by radioimmunoassay (RIA) and prolactin was determined by bioassay in 18 premenopausal women with breast cancer, 23 healthy women with a strong family history of breast cancer, and 39 healthy women with no significant family history of breast cancer. Parity was associated strongly with decreased prolactin levels, and increasing age was associated strongly with decreased growth hormone levels. After controlling for these variables, no differences in prolactin or growth hormone levels were found among the three groups of women. These data do not support roles for these RIA-measured hormones or bioassay-measured prolactin in premenopausal or familial breast cancer in omnivorous white women.
A study of 424 women was undertaken to determine whether there was an association between serum prolactin levels and breast cancer; whether prolactin levels would reflect degrees of risk of developing breast cancer; and whether associations between known risk factors for breast cancer and serum prolactin concentrations could be demonstrated. Prolactin levels higher than the median value in control subjects were found to be associated with a more than two-fold increase in the risk of breast cancer (relative risk, 2.1; confidence interval [CI], 1.0-4.5). Moreover, a relative risk of 1.7 (CI, 0.9-3.3) for a group of women with benign epithelial hyperplasia (high risk of developing breast cancer), and a relative risk of 1.0 (CI, 0.6-1.8) for a group with benign fibrocystic disease (low risk of developing breast cancer), provided supportive evidence that prolactin plays a role in the development of breast cancer. A considerable fall in the concentration of prolactin at menopause was noted, so those women who have an early menopause have a reduced period of exposure to high concentrations of prolactin. Similarly, there was a considerable reduction in prolactin concentration after the first pregnancy. Finally, our results showed that, in premenopausal women, a high intake of saturated fats was associated with a high prolactin concentration. Our study supports the concept that parity, menstrual status, and saturated fat consumption influence a woman's exposure to prolactin and therefore the risk of developing breast cancer.
In order to delineate factors contributing to variation in hormone levels, progesterone and prolactin (PRL) levels from 28 normal women, obtained daily during one menstrual cycle and every 20 minutes during a midluteal 24-hour admission in a subgroup of five subjects, provided a data base for analysis of these variables. Pulsatile analysis of the 24-hour data was conducted using an adaptive-threshold algorithm, and normal reference ranges were generated from randomly selected daily hormone values. Our data verify that inherent variation can significantly alter single random serum levels of reproductive hormones. These variations included menstrual cycle day, circadian influence, pulsatile secretion, assay error, and biologic heterogeneity. Besides the expected day-to-day change in progesterone levels during the luteal phase, seven of ten women exhibited a significant circadian variation in progesterone; however, the time of day of the peak level was not consistent among women. Prolactin levels did not demonstrate any clinically relevant change over the menstrual cycle, but did have a consistent circadian pattern (nocturnal rise) over the 24-hour study period. Pulsatile variation occurred in both progesterone and PRL levels during the 24-hour admission. Five different reference ranges were generated from randomly selected single daily values from the 28 normal menstrual cycles. Although the mean levels calculated for each reference range were similar, the reference ranges demonstrated considerable variation due to the random sampling. In the five progesterone reference ranges, the lower limit of the range varied from 2.7-6.1 ng/mL, whereas the upper limit varied from 24.2-42.1 ng/mL.(ABSTRACT TRUNCATED AT 250 WORDS)
An early first pregnancy is known to protect against subsequent breast cancer. We speculated that this effect may be mediated by a long-term depression of prolactin secretion after pregnancy. We therefore measured basal and post-stimulation serum levels of prolactin, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) in two groups--15 women 18 to 23 years of age and 9 women 29 to 40--before and after a first full-term pregnancy, and in 40 appropriate nulliparous controls. We observed no significant change in basal levels of serum LH or FSH or in the levels stimulated by gonadotropin-releasing hormone in any group. A significant decrease was seen, however, in basal and perphenazine-stimulated levels of prolactin after pregnancy in both the younger and older first-pregnancy groups but not in the controls. In a separate cross-sectional study, we compared basal serum prolactin levels in 29 parous and 19 nulliparous women of similar age. The serum prolactin levels were significantly lower in the parous group but were not related to the number of pregnancies (one to three) or the time elapsed (12 to 150 months) since the last delivery. We conclude that a first pregnancy leads to a long-term decrease in serum prolactin secretion, lasting at least 12 to 13 years.
In each of two population-based studies conducted on the Island of Guernsey between 1967-1976 and 1977-1984, respectively, single specimens of blood were taken from over 5000 normal women. From these two studies there were 1173 and 946 postmenopausal women in whom blood prolactin was determined and multivariate analysis was used to establish the association between blood prolactin concentration and possible determinants of risk of breast cancer. Since prolactin levels were log-normally distributed these analyses were done on log-transformed data. The age at menarche or menopause, age at first or last childbirth, length of reproductive life (i.e. time from menarche to menopause) or post-menopausal life (i.e. time from menopause to time of blood sampling), contraceptive use and history of breast cancer were not significantly associated with blood prolactin concentration. Of significance were age, parity, time of blood sampling and assay drift. Ponderosity (Quetelet's Index) was positively associated with prolactin concentration and this was significant using a one-tail criterion. Women with a mammographic pattern designated DY by Wolfe had significantly higher prolactin levels than those with N1 patterns. However, the main finding to emerge was that after standardizing for all the other variables increasing parity was related to a step-wise reduction in blood prolactin levels. Since this had occurred in women who had had their last child up to 35 years previously it implies this effect is permanent. It could therefore be that the protective effect on breast cancer risk of multiparity and early first pregnancy could be mediated by such a life-long reduction in blood prolactin levels.
Forty-one women with breast cancer and 119 controls participated in a case-control study of the relation of endogenous sex hormones to breast carcinoma in premenopausal women. During the follicular phase of the menstrual cycle, one overnight urine specimen was collected. During the luteal phase, urine and blood specimens were obtained. 17 beta-Estradiol, sex hormone-binding globulin, progesterone, and prolactin were measured in plasma, whereas estrogen metabolites (estrone, estradiol, and estriol) and pregnanediol were assessed in the urine. Breast cancer was associated with high-plasma estradiol and prolactin and with low progesterone. Similar but weaker associations were observed for urinary estrogens and pregnanediol in the luteal phase.
Single specimens of blood have been taken from over 5000 normal volunteer women in each of two sequential (1967-1976, 1977-1984) population-based studied on the Island of Guernsey. Multivariate analysis was used to determine the relationship between prolactin levels and risk factors in breast cancer in 2591 and 1959 premenopausal women in whom blood prolactin had been measured. In both populations the prolactin concentrations appeared to be log-normally distributed and therefore all analyses have been done on log-transformed data. Initially the variables in the statistical model were age at menarche, ages at first and last baby, parity, ponderosity (Quetelet Index), mammographic pattern (as graded by Wolfe), family history of breast cancer, age, menstrual cycle status, time of day of blood sampling, oral contraceptive use, history of breast feeding and methodological changes in the laboratory measurement of prolactin. Of these variables age at menarche, ages at first and last child and family history of breast cancer were found not to be significant and were excluded from the final model. The main finding to emerge was that after standardizing for all the other variables, prolactin levels in the follicular phase were significantly lower than those found at midcycle or during the luteal phase of the menstrual cycle. A peak level of prolactin was found at day 12 of the cycle. Increasing parity was related to a steady decrease in prolactin concentration. Increasing ponderosity was associated with an increased prolactin level as was a DY compared to an N1 mammographic pattern. Women with a history of oral contraceptive use had lowered prolactin concentration. All these effects occurred evenly over the menstrual cycle and were generally found for both data sets. Thus body weight, parity and, indirectly, age at first baby might influence breast cancer risk by being associated with changes in blood prolactin concentration.
The hormone profiles of nulliparous and parous women on day 11 of their menstrual cycle have been studied in an attempt to seek evidence for the hormonal basis of the protective effect of first birth on breast cancer risk. A previous publication reported that there were significantly lower (26%) early morning prolactin levels in parous women as compared to those levels in nulliparous women but that there were no differences in plasma and urinary estrogen levels. The present study shows, however, that parous women had significantly shorter cycle lengths than nulliparous women of the same age, and the data were reevaluated with this difference being taken into account. After adjustment for cycle length (within the range of 24-32 days) and age, estrogen levels were significantly lower (22%) in parous women compared to those in nulliparous women. Two further aspects of estrogen metabolism were measured in the plasma samples of these women: the binding capacity of sex hormone-binding globulin (SHBG) and the percentage of free estradiol (E2). SHBG levels were 12% higher in parous women, but there was no difference in percentage of free E2. In the previous publication it was suggested that the protective effect of first birth on breast cancer risk was mediated in part by permanently lowering prolactin levels. The current findings suggest that changes in estrogen metabolism also are a factor.
Throughout life, the ovarian surface epithelium (OSE) undergoes morphogenetic changes that may be hormonally regulated. To investigate this possibility, a population of cells morphologically identical to native OSE cells was isolated from estrous rabbits with collagenase, unit gravity sedimentation, and trypsin-EDTA. Cells were incubated with various concentrations of protein hormones in serum-rich medium or in a chemically defined medium containing fibronectin. Tritiated thymidine was added 24 h before interruption of cultures. Growth-promoting effects of tested hormones were more pronounced and consistent in serum-free cultures. Under these conditions, human chorionic gonadotropin (10,000 mIU/ml) caused a 2.8-fold increase in cell number and a 3.4-fold stimulation of thymidine incorporation. Luteinizing hormone (NIAMDD-oLH-24, 1.0 micrograms/ml) and follicle-stimulating hormone (NIADDK-oFSH-16, 1.0 micrograms/ml) produced, respectively, a 1.7-fold and 1.5-fold increase in cell proliferation, and over 1.4-fold and 1.3-fold stimulations of thymidine uptake. When used together, no growth stimulation by these gonadotropins was seen. Slight but significant increases in cell number (1.4-fold) and in radiolabel incorporation (1.3-fold) were observed with prolactin (NIADDK-oPrl-16, 10 ng/ml). These data indicate that some protein hormones promote the growth of OSE cells. This property may be important in regulating these cells during normal and pathologic states.
The amount of prolactin has been determined in serial blood samples taken over 24 h from 20 pre- and 9 postmenopausal women volunteers. All women had a large increase in prolactin at night (24.00 h-03.00 h). A much smaller rise in prolactin occurred in the evening (18.00 h-20.00 h) which was just significantly different (p less than 0.05) from levels found in the afternoon. Prolactin concentrations at any given time in the 29 women were linearly correlated with corresponding levels in either of the adjacent time intervals. This correlation was highly significant (p less than 0.001) throughout 24 h, implying that a woman with a relatively high (or low) blood prolactin in the afternoon would have a similarly high (or low) concentration in the evening or at night. Premenopausal women had higher amounts of prolactin than postmenopausal volunteers throughout the day. Parity was found to be inversely related to prolactin levels in pre- and postmenopausal women; this effect was especially marked in the night peak of prolactin. In postmenopausal women an average of 33 years had elapsed since the birth of the last child, which implies that childbirth has a life-long effect on reducing prolactin levels. Thus the protective effect of early child-bearing and multiparity against developing breast cancer could be at least partly explained by these effects on serum prolactin levels.
Twenty-four-hour luteal phase PRL secretion has been evaluated with a frequent sampling technique in 13 women whose mothers had breast cancer and in 13 age- and weight-matched control subjects. Significantly elevated serum PRL levels were noted throughout the day and night in the young women at risk for breast cancer. Also, 10 of the 13 daughters at risk for breast cancer had mean 24-h PRL levels above the highest mean PRL level of the control population. However, most of the hourly PRL levels in the at risk females were within the range of normal. Serum estradiol, progesterone, testosterone, LH, and FSH levels were not different between the two groups. Although stress cannot be excluded as playing a role in the differences in serum PRL levels, the midprofile plasma cortisol levels were similar between the two groups. Since dopamine is a primary regulator of serum PRL levels, the PRL response of the pituitary lactotrophs of those women at risk for breast cancer was studied with dopamine infusions. A dopamine infusion at a rate of 0.004 μg/kg.min produced an initial suppression of serum PRL levels in the at risk subjects. At 120 min, however, their serum PRL levels returned to basal levels, whereas persistent suppression occurred in the control population. In contrast, a higher dose of dopamine, 0.04 μg/kg.min, induced a similar degree of PRL suppression in the controls and at risk females. Serum estradiol levels were similar in both groups on the day of each dopamine infusion. In summary, 1) increased 24-h mean PRL levels have been found in 13 young females whose mothers had breast cancer; 2) in addition, in these women at risk for breast cancer a partial resistance of PRL to dopamine suppression occurred.
Plasma prolactin has been measured in over 3,500 women volunteers from a normal population. In premenopausal women there was a significant decrease in prolactin levels with increasing parity. However, this effect was transitory since plasma prolactin concentration rose with increasing time after the birth of the last child. There were no significant differences in prolactin levels with respect to height and weight, although overweight compared to underweight women had approximately 15% more plasma prolactin. If prolactin is a carcinogen, then these results are in keeping with the epidemiological findings that multiparity affords protection and that age at last delivery is a risk factor in the development of breast cancer.
An investigation was made of daytime plasma prolactin levels in three groups of women aged 50 to 64 years: (1) 139 women with a family history of breast cancer; (2) 50 women on Rauwolfia treatment for hypertension, and (3) 90 women of a control group. A significant difference in prolactin levels was found between groups 2 and 3 but not between 1 and 3. These findings are considered in relation to the results of a breast cancer screening programme in which the women took part. Here, it was the women with a family history of breast cancer who showed an increased breast cancer risk, whereas the risk in women on Rauwolfia was not significantly higher than expected on the basis of the experience among controls. It is concluded that the role of prolactin in the etiology of breast cancer is still not clear.
Parity, age at first birth, age at menarche, and a family history of breast cancer have each been associated consistently with breast cancer risk. Whether this increase in risk is mediated, at least in part, through changes in endogenous hormone levels is unclear. We conducted a cross-sectional study of the relationships between these factors and plasma hormone levels in 216 healthy postmenopausal women in the Nurses' Health Study (United States). The hormones evaluated were estradiol, percent and total free estradiol, percent and total bioavailable estradiol, estrone, estrone sulfate, and prolactin. After controlling for age, body mass index (weight/height2), and alcohol use, we observed inverse associations between estrone sulfate and parity (r = -0.15, P = 0.03) and between percent bioavailable estradiol and age at first birth (r = -0.17, P = 0.02). Although women with a family history of breast cancer tended to have higher estrogen levels compared with women without such history, the differences were not statistically significant. Age at menarche was not related significantly to any of the hormones. These data provide some additional evidence that the inverse relationship observed between parity and breast cancer risk may be mediated, at least in part, through decreased estrogen levels. Our data do not support a substantial influence of either family history of breast cancer or age at menarche on postmenopausal estrogen or prolactin levels.
To analyze the role of individual glycosylation pattern on PRL biopotency, monomeric prolactin (PRL), secreted by human prolactinoma cells in culture, was isolated by gel filtration and separated by affinity chromatography on Concanavalin A-Sepharose or Lentil-Agarose. These lectins allowed the isolation of PRL glycoforms containing either biantennary, mannose-rich or fucosylated complex carbohydrate structures, respectively. Endoglycosidase treatment and carbohydrate content of PRL was found to be consistent with N-linked oligosaccharides of mannose-rich structure and complex units terminated in sialic acid. Mannose-rich PRL and PRL with biantennary oligosaccharides promoted cell growth of rat lymphoma cells to a diminished extent compared to non-glycosylated PRL (NG-PRL), indicating that the two major types of carbohydrate structure are able to decrease the intrinsic bioactivity of PRL. Metabolic clearance of the various forms of PRL in rats was also found to be highly dependent upon hormone glycosylation. The various glycosylated forms (G-PRLs) proved to be totally eliminated from the circulation within 60 min, faster than NG-PRL 10% of which was still present at that time. Mannose-rich or biantennary G-PRLs were differently cleared in a biphasial fashion with a similar rapid phase of about 2 min followed by distinct slow phases of 12 and 27 min, respectively. The presence of fucose did not alter this distribution. In contrast, NG-PRL was eliminated with a half-time of approximately 5 min, followed by a very slow disappearance over several h. It thus appeared that glycosylation increased the metabolic clearance rate of PRL from 0.13 +/- 0.07 ml/min for NG-PRL to 0.47 +/- 0.12 ml/min for PRL with biantennary carbohydrate chains and 0.8 +/- 0.2 ml/min for the hormone with mannose-rich oligosaccharides. The distribution of PRL to target and elimination organs was also found to be different according to the carbohydrate structure present in the hormone. NG-PRL and mannose-rich G-PRL showed higher incorporation in liver than biantennary G-PRL which was preferentially eliminated by the kidney. Altogether, the current data show that addition of oligosaccharides to PRL as well as carbohydrate structure contribute to modulate both the duration of the hormone in the blood and its distribution to different organs. It is proposed that glycosylation may selectively down-regulate PRL action at individual target tissues.
Serum hormones have been intensively investigated in association with several chronic diseases, but limited information exists on the reliability of a number of hormone determinations. The one-year reproducibility of dehydroepiandrosterone sulfate (DHEAS), total and free testosterone, total estradiol, insulin, C-peptide, and prolactin was studied in 60 premenopausal and 47 postmenopausal women recruited in Varese province, Italy, 1991-1992. The hormonal determinations were made in blood samples collected twice, one year apart, after 12-h fast, in the same month, day, and hour and for premenopausal women on the same day of the luteal phase of the menstrual cycle. Samples from the first drawing were stored at -80 degrees C. Samples from both drawings were assayed simultaneously and in blind fashion. Total estradiol in postmenopause was not evaluated for limitation in the sensitivity of the laboratory method. The intraclass correlation coefficient in premenopausal women was 0.85 for DHEAS, 0.60 for total testosterone, 0.66 for free testosterone, 0.81 for insulin, 0.83 for C-peptide, 0.40 for prolactin, and 0.06 for total estradiol. In postmenopausal women, the coefficient was 0.90 for DHEAS, 0.88 for total testosterone, 0.71 for free testosterone, 0.67 for insulin, 0.73 for C-peptide, and 0.18 for prolactin. These data indicate that total estradiol measured during the luteal phase has a poor intraindividual reproducibility over time, and these findings may have important implications in studies of hormones in the etiology of chronic disease.
To investigate intraovarian prolactin and prolactin-receptor gene expression and to assess local prolactin synthesis with emphasis on possible differences between premenopausal and postmenopausal status.
The RNA extracted from human premenopausal and postmenopausal tissues was subjected to reverse transcription and polymerase chain reaction by using prolactin-specific intron- and exon-spanning primers. Prolactin-receptor expression was investigated accordingly. The amplified complementary DNA fragments were analyzed by gel electrophoresis and restriction enzyme mapping. Local prolactin hormone synthesis was verified by a time-resolved immunofluorometric assay based on our monoclonal antibodies.
Prolactin and prolactin-receptor gene expression was observed in all analyzed human ovaries (n = 18). Several other human tissue specimens, such as lung and kidney, served as negative control tissues. Significantly elevated concentrations of prolactin were detected in cytosolic extracts of premenopausal (n = 6; mean +/- SD; 20.6 +/- 3.3 ng/g tissue wet weight) versus postmenopausal (n = 6; 3.6 +/- 3.0 ng/g tissue wet weight) ovaries.
The human ovary not only serves as a target for endocrine prolactin action but also as a site of local prolactin hormone production. In agreement with previous reports on extrapituitary sources of prolactin, we consider prolactin as a hormone as well as an autocrine or paracrine growth or regulatory factor. Significantly increased concentrations of prolactin in premenopausal ovarian tissue verifies its role in human reproduction.
Differences in hormonal and constitutional parameters between women with at least one first and/or second degree relative with breast cancer (RBC) and women without such affected relatives were studied in a group of healthy, nulligravid women aged 19-25 years. Present oral contraceptive (OC) users were analysed separately. In women not presently exposed to OCs we found significant correlations between RBC and reduced concentrations of testosterone during both the follicular (P < 0.001) and luteal menstrual cycle phases (P = 0.016). 17 beta-oestradiol was also significantly negatively correlated with RBC in the follicular (P = 0.044) and in the luteal phase (P = 0.027). RBC was significantly correlated with a lower waist/hip ratio (P = 0.044) compared with women without such a history. In multivariate analyses, the results for testosterone but not 17 beta-oestradiol remained significant. In these analyses high IGF-1 (P = 0.05) in the follicular phase and low sexual hormone-binding globulin (SHBG) (P = 0.04) in the luteal phase were also related to RBC. Including all 66 women in a multivariate model that analysed the specific effects from OCs and RBC on plasma testosterone showed that plasma testosterone was significantly lower among present OC users (P = 0.004) and in women with RBC (P = 0.005) during cycle days 5-10, with a significant positive two-way interaction between present OC use and RBC (P = 0.007). During cycle days 18-23 plasma testosterone showed a significant negative relationship with present OC use (P < 0.001) and RBC (P = 0.016) no significant interaction was seen during cycle days 18-23. Factors not significantly related to RBC were height, weight, breast size, age at menarche, p-progesterone and p-prolactin. It is concluded that a family history of breast cancer significantly lowered plasma testosterone concentrations in both cycle phases among healthy, nulligravid women compared with women without such history.
The aim of this study was to clarify the significance of serum prolactin concentrations in patients with infertility and endometriosis. Forty patients with infertility and laparoscopically proven endometriosis were recruited into the study. Basal serum prolactin levels and prolactin levels after TRH administration were measured. The mean basal serum prolactin concentrations were 12.5, 16.5, 19.5, and 26.5 ng/ml and those after thyrotropin-releasing hormone (TRH) administration were 88.3, 114.2, 125.3 and 138.8 ng/ml in patients with stages I, II, III and IV endometriosis, respectively. A statistically significant relationship was found between the basal serum prolactin levels as well as those after TRH injection and the stage of the endometriosis. The patients were divided in two groups. Group I consisted of 20 patients who did not receive any treatment, while group II consisted of 20 patients who were initially treated with GnRH analogues for 24 week and subsequently with several therapeutic schemes in order to improve their fecundity. The pregnancy rate was not different between the two groups. The patients, however, who did not become pregnant had higher serum prolactin concentrations after TRH administration as compared to those who conceived. We conclude that occult hyperprolactinemia may be a cause of infertility in patients with endometriosis.
Prolactin, a peptide hormone essential for the development and function of reproductive organs, is involved in development of breast, prostate and colorectal cancers. However, the role of prolactin on the carcinogenesis of ovarian carcinomas is unclear. In this study, we show that mRNA of prolactin receptor is expressed in 5 out of 9 ovarian carcinoma cell lines, 15 out of 17 cases of surgical samples and all of normal ovarian surface epithelium, while prolactin transcript is detected only in 1 ovarian carcinoma cell line and in 1 of the surgical samples. For the prolactin receptor-positive ovarian carcinoma cells, exogenous prolactin did not affect the proliferation but markedly inhibited apoptosis. Therefore, actual cell growth was enhanced by prolactin in a dose-dependent manner. The blocking of prolactin receptor by antibody severely impaired the antiapoptotic and growth-promoting effects of prolactin. Interestingly, the cisplatin-induced cell death of the prolactin receptor-positive cells was significantly inhibited by pretreatment with prolactin. These findings indicate a responsiveness of ovarian carcinomas to prolactin and suggest that the prolactin/prolactin receptor system may be a new therapeutic target of ovarian carcinomas.