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.

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Prolactin: Structure, Function, and Regulation of Secretion

ContextPatients with serum thyroid-stimulating hormone (TSH) levels outside
the reference range and levels of free thyroxine (FT4) and triiodothyronine
(T3) within the reference range are common in clinical practice.
The necessity for further evaluation, possible treatment, and the urgency
of treatment have not been clearly established.ObjectivesTo define subclinical thyroid disease, review its epidemiology, recommend
an appropriate evaluation, explore the risks and benefits of treatment and
consequences of nontreatment, and determine whether population-based screening
is warranted.Data SourcesMEDLINE, EMBASE, Biosis, the Agency for Healthcare Research and Quality,
National Guideline Clearing House, the Cochrane Database of Systematic Reviews
and Controlled Trials Register, and several National Health Services (UK)
databases were searched for articles on subclinical thyroid disease published
between 1995 and 2002. Articles published before 1995 were recommended by
expert consultants.Study Selection and Data ExtractionA total of 195 English-language or translated papers were reviewed.
Editorials, individual case studies, studies enrolling fewer than 10 patients,
and nonsystematic reviews were excluded. Information related to authorship,
year of publication, number of subjects, study design, and results were extracted
and formed the basis for an evidence report, consisting of tables and summaries
of each subject area.Data SynthesisThe strength of the evidence that untreated subclinical thyroid disease
is associated with clinical symptoms and adverse clinical outcomes was assessed
and recommendations for clinical practice developed. Data relating the progression
of subclinical to overt hypothyroidism were rated as good, but data relating
treatment to prevention of progression were inadequate to determine a treatment
benefit. Data relating a serum TSH level higher than 10 mIU/L to elevations
in serum cholesterol were rated as fair but data relating to benefits of treatment
were rated as insufficient. All other associations of symptoms and benefit
of treatment were rated as insufficient or absent. Data relating a serum TSH
concentration lower than 0.1 mIU/L to the presence of atrial fibrillation
and progression to overt hyperthyroidism were rated as good, but no data supported
treatment to prevent these outcomes. Data relating restoration of the TSH
level to within the reference range with improvements in bone mineral density
were rated as fair. Data addressing all other associations of subclinical
hyperthyroid disease and adverse clinical outcomes or treatment benefits were
rated as insufficient or absent. Subclinical hypothyroid disease in pregnancy
is a special case and aggressive case finding and treatment in pregnant women
can be justified.ConclusionsData supporting associations of subclinical thyroid disease with symptoms
or adverse clinical outcomes or benefits of treatment are few. The consequences
of subclinical thyroid disease (serum TSH 0.1-0.45 mIU/L or 4.5-10.0 mIU/L)
are minimal and we recommend against routine treatment of patients with TSH
levels in these ranges. There is insufficient evidence to support population-based
screening. Aggressive case finding is appropriate in pregnant women, women
older than 60 years, and others at high risk for thyroid dysfunction.

https://jamanetwork.com/journals/jama/articlepdf/197994/JSR30016.pdf

Subclinical thyroid disease: scientific review and guidelines for diagnosis and management.

Objective: The aim was to update the guidelines for the management of thyroid dysfunction during pregnancy and postpartum published previously in 2007. A summary of changes between the 2007 and 2012 version is identified in the Supplemental Data (published on The Endocrine Society's Journals Online web site at http://jcem.endojournals.org). Evidence: This evidence-based guideline was developed according to the U.S. Preventive Service Task Force, grading items level A, B, C, D, or I, on the basis of the strength of evidence and magnitude of net benefit (benefits minus harms) as well as the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence. Consensus Process: The guideline was developed through a series of e-mails, conference calls, and one face-to-face meeting. An initial draft was prepared by the Task Force, with the help of a medical writer, and reviewed and commented on by members of The Endocri...

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Management of Thyroid Dysfunction during Pregnancy and Postpartum: An Endocrine Society Clinical Practice Guideline

We used longitudinal data from the Massachusetts Male Aging Study, a large population-based random-sample cohort of men aged 40-70 yr at baseline, to establish normative age trends for serum level of T and related hormones in middle-aged men and to test whether general health status affected the age trends. Of 1,709 men enrolled in 1987-1989, 1,156 were followed up 7-10 yr afterward. By repeated-measures statistical analysis, we estimated simultaneously the cross-sectional age trend of each hormone between subjects within the baseline data, the cross-sectional trend between subjects within the follow-up data, and the longitudinal trend within subjects between baseline and follow-up. Total T declined cross-sectionally at 0.8%/yr of age within the follow-up data, whereas both free and albumin-bound T declined at about 2%/yr, all significantly more steeply than within the baseline data. Sex hormone-binding globulin increased cross-sectionally at 1.6%/yr in the follow-up data, similarly to baseline. The longitudinal decline within subjects between baseline and follow-up was considerably steeper than the cross-sectional trend within measurement times for total T (1.6%/yr) and bioavailable T (2-3%/yr). Dehydroepiandrosterone, dehydroepiandrosterone sulfate, cortisol, and estrone showed significant longitudinal declines, whereas dihydrotestosterone, pituitary gonadotropins, and PRL rose longitudinally. Apparent good health, defined as absence of chronic illness, prescription medication, obesity, or excessive drinking, added 10-15% to the level of several androgens and attenuated the cross-sectional trends in T and LH but did not otherwise affect longitudinal or cross-sectional trends. The paradoxical finding that longitudinal age trends were steeper than cross-sectional trends suggests that incident poor health may accelerate the age-related decline in androgen levels.

/pdf/age-trends-in-the-level-of-serum-testosterone-and-other-4b78ypd3j4.pdf

Age Trends in the Level of Serum Testosterone and Other Hormones in Middle-Aged Men: Longitudinal Results from the Massachusetts Male Aging Study

Nutrition is one of the main regulators of circulating IGF-I. In humans, serum IGF-I concentrations are markedly lowered by energy and/or protein deprivation. Both energy and proteins are critical in the regulation of serum IGF-I concentrations. Indeed, after fasting, optimal intake of both energy and protein is necessary for the rapid restoration of circulating IGF-I. We believe, however, that in adult humans energy may be somewhat more important than protein in this regard. While the lowest protein intake is able to increase IGF-I in the presence of adequate energy, there is a threshold energy requirement below which optimal protein intake fails to raise IGF-I after fasting. When energy intake is severely reduced, the carbohydrate content of the diet is a major determinant of responsiveness of IGF-I to GH. The essential amino acid content of the diet is also critical for the optimal restoration of IGF-I after fasting, when protein intake is reduced. The exquisite sensitivity of circulating IGF-I to nutrients, the nycthemeral stability of its concentrations and its relative short half-life constitute the basis for its use as a marker of both nutritional status and adequacy of nutritional rehabilitation. For these indications, IGF-I measurement is more sensitive and more specific than measurement of the other nutrient-related serum proteins (albumin, prealbumin, transferrin, retinol-binding protein). Animal models have been developed to investigate the mechanisms responsible for the nutritional regulation of IGF-I. There is no doubt that many mechanisms are involved (Fig. 12). Decline of serum IGF-I in dietary restriction is independent of the diet-induced alterations in pituitary GH secretion. The role of the liver GH receptors is dependent on the severity of the nutritional insult. In severe dietary restriction (fasting), a marked decrease of the number of somatogenic receptors supports the role of a receptor defect in the decline of circulating IGF-I. In contrast, in less severe forms of dietary restriction (protein restriction), the decline of IGF-I results from a postreceptor defect in the GH action at the hepatic level. Nutritional deprivation decreases hepatic IGF-I production by diminishing IGF-I gene expression. Decline in IGF-I gene expression is mainly caused by nutrient deficiency and less importantly by the nutritionally induced hormonal changes (insulin and T3). Diet restriction also increases the clearance and degradation of serum IGF-I through changes in the levels of circulating IGFBPs.(ABSTRACT TRUNCATED AT 400 WORDS)

Nutritional Regulation of the Insulin-Like Growth Factors*

A prospective study was undertaken in 606 healthy women during pregnancy to evaluate the changes occurring in maternal thyroid economy as a result of 1) the increased thyroid hormone-binding capacity of serum, 2) the effects of increased levels of hCG on TSH and on the thyroid, and 3) a marginally low iodine intake in the population (50-75 micrograms/day). Four main features were observed. First, thyroidal activity adjusted to the marked increase in serum T4-binding globulin: pregnancy was accompanied by an overall reduction in the T4/T4-binding globulin ratio, with lower free T4 and T3 levels, although in most cases free hormone levels remained within the normal range. The adjustment of thyroidal output of T4 and T3 did not occur similarly in all subjects. In approximately one third of the women, there was relative hypothyroxinemia, higher T3/T4 ratios (presumably indicating preferential T3 secretion), and higher, although normal, serum TSH concentrations. Second, high hCG levels were associated with thyroid stimulation, both functionally (lower serum TSH) and anatomically (increased thyroid size). The data are consistent with a TSH-like effect of hCG on the thyroid. Hence, regulation of the maternal thyroid is complex, resulting from both elevated hCG (mainly in the first half of gestation) and increasing TSH (mainly in the second half of gestation). Third, a significant increase in serum thyroglobulin levels was observed throughout gestation, especially during the last trimester. Fourth, increased thyroid volume was common, and goiter formation not uncommon (goiter was found in 9% of women at delivery). In conclusion, the alterations in maternal thyroid function during gestation are intricate and far from fully understood. In areas of marginally low iodine intake, gestation is associated in a significant number of women with relative hypothyroxinemia, increased thyroglobulin, and enlarged thyroid.

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Regulation of Maternal Thyroid during Pregnancy

The main objective of the present study was to present additional evidence of the potentially important thyrotropic role of hCG to regulate the maternal thyroid gland during normal pregnancy. Sequential determinations (first and last trimesters) of intact hCG, free alpha and beta-hCG subunits concentrations (using monoclonal IRMAs), and assessment of parameters of thyroid function and thyroid volume were carried out in 62 pregnant women who exhibited during the first trimester of gestation low TSH levels (< or = 0.20 mU/L), and compared to 276 pregnant women with normal TSH levels. The prevalence of having low serum TSH represented 18% of all pregnancies, with almost one half of cases who transiently had undetectable TSH levels. Lowering of TSH was associated with high hCG levels, and occurred primarily during the first trimester. About 10% of women with low TSH presented transient gestational thyrotoxicosis, frequently associated with vomiting. In comparison to control subjects, women with a suppressed serum TSH had significantly and markedly higher intact hCG and free beta-hCG subunit concentrations. The results suggest that TSH reduction may result from a relative oversecretion of both intact hCG and free beta-hCG subunits, compatible with three hypotheses: a) transient overexpression of the beta-hCG gene, leading to enhanced production of hCG heterodimer; b) increased glycosylation of circulating hCG, with in turn a prolonged half life; c) larger syncytiotrophoblast mass with increased hCG production.(ABSTRACT TRUNCATED AT 250 WORDS)

Serum Levels of Intact Human Chorionic-gonadotropin (hcg) and its Free-alpha and Beta-subunits, in Relation To Maternal Thyroid-stimulation During Normal-pregnancy

Case 1-A 51-year-old woman was admitted for cholecystectomy; at operation a peroperative choledochogram showed an enlarged duct with the suspicion of a stone within it. Formal supraduodenal exploration, together with transduodenal sphincterotomy, was performed and two stones removed. The post operative T-tube choledochogram showed two residual stones in the lower end of the duct. Three washouts were performed over the next few days and a T-tube choledochogram after the last washout showed no evidence of residual calculi. The T-tube was removed and the patient has remained well. Case 2-This man presented with recurrent episodes of cholangitis. At operation the choledochogram showed a stone in the lower end of the duct but none was found on exploration and transduodenal sphincterotomy. Two postoperative T-tube choledochograms showed two residual stones in the lower end of the bile duct. Re-exploration was performed and one crushed stone removed. A repeat choledochogram showed one residual stone and a biliary washout was then performed. A T-tube choledochogram two days later showed free flow of the contrast medium into the duodenum and no evidence of the residual stone. The T-tube was removed and the patient has remained well.

https://www.bmj.com/content/bmj/4/5999/738.full.pdf

Influence of age on serum prolactin levels in women and men.

Immunoreactive human serum prolactin of pituitary origin has been measured by a radioimmunoassay developed for ovine prolactin. Blood samples were collected at four-hour intervals during a 24-hour period from 12 non-pregnant women, three pregnant women, and seven adult men. A circadian periodicity was found in serum prolactin concentration, with peak values during the night, between 1 a.m. and 5 a.m. for the non-pregnant women, and at 5 a.m. for the adult men. Mean serum levels of prolactin were 1·5 times higher in non-pregnant women than in men. In women investigated during the last month of their pregnancy the mean serum prolactin levels were 2·3 times higher than in the non-pregnant women, but there was no circadian periodicity.

https://www.bmj.com/content/bmj/3/5826/561.full.pdf

Circadian Periodicity of Serum Prolactin Concentration in Man

Serum prolactin has been measured in blood samples collected daily during 51 menstrual cycles using an homologous human radioimmunoassay for 17 cycles and an homologous ovine radioimmunoassay for 34 cycles. There was a progressive and significant increase in serum prolactin during the late follicular phase, with a maximal value concomitant to the LH peak. Serum prolactin levels were also significantly higher during the luteal phase than during early follicular phase. In some 70% of the individual cycles, the highest serum prolactin level was found at mid-cycle. Similar patterns were obtained with both radioimmunoassays. However, when using the same laboratory serum standard, the average serum prolactin level calculated for the entire cycle was 1.6 times higher with the homologous ovine assay than with the homologous human assay. The overall pattern of serum prolactin during the menstrual cycle resembles that reported for circulating 17beta-estradiol.

Claude Robyn

Papers

Regulation of Maternal Thyroid during Pregnancy

Serum Levels of Intact Human Chorionic-gonadotropin (hcg) and its Free-alpha and Beta-subunits, in Relation To Maternal Thyroid-stimulation During Normal-pregnancy

Influence of age on serum prolactin levels in women and men.

Circadian Periodicity of Serum Prolactin Concentration in Man

Serum prolactin levels during the menstrual cycle.