Hyperprolactinemia

Prl

Lactotropes and somatotropes are derived from a common precursor cell that may give rise to a tumor secreting both PRL and GH. Marked lactotrope cell hyperplasia develops during the last two trimesters of pregnancy and the first few months of lactation. These transient functional changes in the lactotrope population are induced by estrogen

Normal adult serum PRL levels are about 10–25 g/L in women and 10–20 g/L in men. PRL secretion is pulsatile, with the highest secretory peaks occurring during rapid eye movement sleep. Peak serum PRL levels (up to 30 g/L) occur between 4:00 and 6:00 A.M. The circulating half-life of PRL is about 50 min

PRL is unique among the pituitary hormones in that the predominant central control mechanism is inhibitory, reflecting dopamine-mediated suppression of PRL release. This regulatory pathway accounts for the spontaneous PRL hypersecretion that occurs after pituitary stalk section, often a consequence of compressive mass lesions at the skull base. Pituitary, dopamine type 2 (D₂) receptors mediate PRL inhibition.

Thyrotropin-releasing hormone (TRH) (pyro Glu-His-Pro-NH2) is a hypothalamic tripeptide that releases prolactin within 15–30 min after intravenous injection. The physiologic relevance of TRH for PRL regulation is unclear, and it appears primarily to regulate TSH (Chap. 335). Vasoactive intestinal peptide (VIP) also induces PRL release, whereas glucocorticoids and thyroid hormone weakly suppress PRL secretion.

PRL levels increase significantly (about tenfold) during pregnancy and decline rapidly within 2 weeks of parturition. If breastfeeding is initiated, basal PRL levels remain elevated; suckling stimulates reflex increases in PRL levels that last for about 30–45 min. Breast suckling activates neural afferent pathways in the hypothalamus that induce PRL release. With time, the suckling-induced responses diminish and interfeeding PRL levels return to normal

In the breast, the lobuloalveolar epithelium proliferates in response to PRL, placental lactogens, estrogen, progesterone, and local paracrine growth factors, including IGF-I.

PRL acts to induce and maintain lactation, decrease reproductive function, and suppress sexual drive. These functions are geared toward ensuring that maternal lactation is sustained and not interrupted by pregnancy. PRL inhibits reproductive function by suppressing hypothalamic GnRH and pituitary gonadotropin secretion and by impairing gonadal steroidogenesis in both women and men. In the ovary, PRL blocks folliculogenesis and inhibits granulosa cell aromatase activity, leading to hypoestrogenism and anovulation. PRL also has a luteolytic effect, generating a shortened, or inadequate, luteal phase of the menstrual cycle. In men, attenuated LH secretion leads to low testosterone levels and decreased spermatogenesis. These hormonal changes decrease libido and reduce fertility in patients with hyperprolactinemia.

Hyperprolactinemia

Hyperprolactinemia is the most common pituitary hormone hypersecretion syndrome in both men and women. PRL-secreting pituitary adenomas (prolactinomas) are the most common cause of PRL levels >100 g/L (see below). Less pronounced PRL elevation can also be seen with microprolactinomas but is more commonly caused by drugs, pituitary stalk compression, hypothyroidism, or renal failure

Pregnancy and lactation are the important physiologic causes of hyperprolactinemia. Sleep-associated hyperprolactinemia reverts to normal within an hour of awakening. Nipple stimulation and sexual orgasm may also increase PRL. Chest wall stimulation or trauma (including chest surgery and herpes zoster) invoke the reflex suckling arc with resultant hyperprolactinemia. Chronic renal failure elevates PRL by decreasing peripheral clearance. Primary hypothyroidism is associated with mild hyperprolactinemia, probably because of compensatory TRH secretion

Drug-induced inhibition or disruption of dopaminergic receptor function is a common cause of hyperprolactinemia (Table 333-8). Thus, antipsychotics and antidepressants are a relatively common cause of mild hyperprolactinemia. Methyldopa inhibits dopamine synthesis and verapamil blocks dopamine release, also leading to hyperprolactinemia. Hormonal agents that induce PRL include estrogens, antiandrogens, and TRH

Amenorrhea, galactorrhea, and infertility are the hallmarks of hyperprolactinemia in women. If hyperprolactinemia develops prior to menarche, primary amenorrhea results. More commonly, hyperprolactinemia develops later in life and leads to oligomenorrhea and, ultimately, to amenorrhea. If hyperprolactinemia is sustained, vertebral bone mineral density can be reduced compared with age-matched controls, particularly when associated with pronounced hypoestrogenemia. Galactorrhea is present in up to 80% of hyperprolactinemic women. Although usually bilateral and spontaneous, it may be unilateral or only expressed manually. Patients may also complain of decreased libido, weight gain, and mild hirsutism.

In men with hyperprolactinemia, diminished libido, infertility, or visual loss (from optic nerve compression) are the usual presenting symptoms. Gonadotropin suppression leads to reduced testosterone, impotence, and oligospermia. True galactorrhea is uncommon in men with hyperprolactinemia. If the disorder is longstanding, secondary effects of hypogonadism are evident, including osteopenia, reduced muscle mass, and decreased beard growth.

The diagnosis of idiopathic hyperprolactinemia is made by exclusion of known causes of hyperprolactinemia in the setting of a normal pituitary MRI. Some of these patients may harbor small microadenomas below MRI sensitivity (~2 mm).

Galactorrhea, the inappropriate discharge of milk-containing fluid from the breast, is considered abnormal if it persists for longer than 6 months after childbirth or discontinuation of breastfeeding. Mammography or ultrasound is indicated for bloody discharges (particularly from a single duct), which may be caused by breast cancer.

Prolactinoma

Microadenomas are classified as <1>1 cm in diameter and may be locally invasive and impinge on adjacent structures. The female:male ratio for microprolactinomas is 20:1, whereas the gender ratio is near 1:1 for macroadenomas. Tumor size generally correlates directly with PRL concentrations; values >100 g/L are usually associated with macroadenomas. About 5% of microadenomas progress in the long term to macroadenomas. Hyperprolactinemia resolves spontaneously in about 30% of microadenomas

Women usually present with amenorrhea, infertility, and galactorrhea. If the tumor extends outside of the sella, visual field defects or other mass effects may be seen. Men often present with impotence, loss of libido, infertility, or signs of central CNS compression including headaches and visual defects. Assuming that physiologic and medication-induced causes of hyperprolactinemia are excluded (Table 333-8), the diagnosis of prolactinoma is likely with a PRL level >100 g/L. PRL levels <100>

For symptomatic microadenomas, therapeutic goals include control of hyperprolactinemia, reduction of tumor size, restoration of menses and fertility, and resolution of galactorrhea. Dopamine agonist doses should be titrated to achieve maximal PRL suppression and restoration of reproductive function (Fig. 333-6). A normalized PRL level does not ensure reduced tumor size. However, tumor shrinkage is not usually seen in those who do not respond with lowered PRL levels. For macroadenomas, formal visual field testing should be performed before initiating dopamine agonists. MRI and visual fields should be assessed at 6- to 12-month intervals until the mass shrinks and annually thereafter until maximum size reduction has occurred.

Oral dopamine agonists (cabergoline or bromocriptine) are the mainstay of therapy for patients with micro- or macroprolactinomas. Dopamine agonists suppress PRL secretion and synthesis as well as lactotrope cell proliferation.

Cabergoline

An ergoline derivative, cabergoline is a long-acting dopamine agonist with high D₂ receptor affinity. The drug effectively suppresses PRL for >14 days after a single oral dose and induces prolactinoma shrinkage in most patients. Cabergoline (0.5 to 1.0 mg twice weekly) achieves normoprolactinemia and resumption of normal gonadal function in ~80% of patients with microadenomas; galactorrhea improves or resolves in 90% of patients. Cabergoline normalizes PRL and shrinks ~70% of macroprolactinomas. Mass effect symptoms, including headaches and visual disorders, usually improve dramatically within days after cabergoline initiation; improvement of sexual function requires several weeks of treatment but may occur before complete normalization of prolactin levels. After initial control of PRL levels has been achieved, cabergoline should be reduced to the lowest effective maintenance dose

Bromocriptine

The ergot alkaloid bromocriptine mesylate is a dopamine receptor agonist that suppresses prolactin secretion. Because it is short-acting, the drug is preferred when pregnancy is desired. In microadenomas bromocriptine rapidly lowers serum prolactin levels to normal in up to 70% of patients, decreases tumor size, and restores gonadal function. In patients with macroadenomas, prolactin levels are also normalized in 70% of patients and tumor mass shrinkage (50%) is achieved in up to 40% of patients.

Therapy is initiated by administering a low bromocriptine dose (0.625–1.25 mg) at bedtime with a snack, followed by gradually increasing the dose. Most patients are successfully controlled with a daily dose of 7.5 mg (2.5 mg tid).

The pituitary increases in size during pregnancy, reflecting the stimulatory effects of estrogen and perhaps other growth factors. About 5% of microadenomas significantly increase in size, but 15–30% of macroadenomas grow during pregnancy. Bromocriptine has been used for more than 30 years to restore fertility in women with hyperprolactinemia, without evidence of teratogenic effects. Nonetheless, most authorities recommend strategies to minimize fetal exposure to the drug. For women taking bromocriptine who desire pregnancy, mechanical contraception should be used through three regular menstrual cycles to allow for conception timing. When pregnancy is confirmed, bromocriptine should be discontinued and PRL levels followed serially, especially if headaches or visual symptoms occur. As cabergoline is long-acting with a high D₂-receptor affinity, it is not approved for use in women when fertility is desired.

Hypopituitarism

Acquired Hypopituitarism

Inflammatory Lesions

Pituitary damage and subsequent dysfunction can be seen with chronic infections such as tuberculosis, with opportunistic fungal infections associated with AIDS, and in tertiary syphilis. Other inflammatory processes, such as granulomas or sarcoidosis, may mimic the features of a pituitary adenoma. These lesions may cause extensive hypothalamic and pituitary damage, leading to trophic hormone deficiencies.

Cranial Irradiation

Cranial irradiation may result in long-term hypothalamic and pituitary dysfunction, especially in children and adolescents, as they are more susceptible to damage following whole-brain or head and neck therapeutic irradiation. The development of hormonal abnormalities correlates strongly with irradiation dosage and the time interval after completion of radiotherapy. Up to two-thirds of patients ultimately develop hormone insufficiency after a median dose of 50 Gy (5000 rad) directed at the skull base. The development of hypopituitarism occurs over 5–15 years and usually reflects hypothalamic damage rather than primary destruction of pituitary cells. Although the pattern of hormone loss is variable, GH deficiency is most common, followed by gonadotropin and ACTH deficiency. When deficiency of one or more hormones is documented, the possibility of diminished reserve of other hormones is likely. Accordingly, anterior pituitary function should be evaluated over the long term in previously irradiated patients, and replacement therapy instituted when appropriate (see below).

Lymphocytic Hypophysitis

This often occurs in postpartum women; it usually presents with hyperprolactinemia and MRI evidence of a prominent pituitary mass often resembling an adenoma, with mildly elevated PRL levels. Pituitary failure caused by diffuse lymphocytic infiltration may be transient or permanent but requires immediate evaluation and treatment. Rarely, isolated pituitary hormone deficiencies have been described, suggesting a selective autoimmune process targeted to specific cell types. Most patients manifest symptoms of progressive mass effects with headache and visual disturbance. The erythrocyte sedimentation rate is often elevated. As the MRI image may be indistinguishable from that of a pituitary adenoma, hypophysitis should be considered in a postpartum woman with a newly diagnosed pituitary mass before embarking on unnecessary surgical intervention. The inflammatory process often resolves after several months of glucocorticoid treatment, and pituitary function may be restored, depending on the extent of damage.

Pituitary Apoplexy

Acute intrapituitary hemorrhagic vascular events can cause substantial damage to the pituitary and surrounding sellar structures. Pituitary apoplexy may occur spontaneously in a preexisting adenoma; post-partum (Sheehan's syndrome); or in association with diabetes, hypertension, sickle cell anemia, or acute shock. The hyperplastic enlargement of the pituitary during pregnancy increases the risk for hemorrhage and infarction. Apoplexy is an endocrine emergency that may result in severe hypoglycemia, hypotension, central nervous system (CNS) hemorrhage, and death. Acute symptoms may include severe headache with signs of meningeal irritation, bilateral visual changes, ophthalmoplegia, and, in severe cases, cardiovascular collapse and loss of consciousness. Pituitary computed tomography (CT) or MRI may reveal signs of intratumoral or sellar hemorrhage, with deviation of the pituitary stalk and compression of pituitary tissue.

Empty Sella

A partial or apparently totally empty sella is often an incidental MRI finding. These patients usually have normal pituitary function, implying that the surrounding rim of pituitary tissue is fully functional. Hypopituitarism, however, may develop insidiously. Pituitary masses may undergo clinically silent infarction with development of a partial or totally empty sella by cerebrospinal fluid (CSF) filling the dural herniation. Rarely, small but functional pituitary adenomas may arise within the rim of pituitary tissue, and these are not always visible on MRI

For example, low free thyroxine in the setting of a low or inappropriately normal TSH level suggests secondary hypothyroidism. Similarly, a low testosterone level without elevation of gonadotropins suggests hypogonadotropic hypogonadism. Provocative tests may be required to assess pituitary reserve (Table 333-3). GH responses to insulin-induced hypoglycemia, arginine, L-dopa, growth hormone–releasing hormone (GHRH), or growth hormone–releasing peptides (GHRPs) can be used to assess GH reserve. Corticotropin-releasing hormone (CRH)

administration induces ACTH release, and administration of synthetic ACTH (cortrosyn) evokes adrenal cortisol release as an indirect indicator of pituitary ACTH reserve (Chap. 336). ACTH reserve is most reliably assessed during insulin-induced hypoglycemia. However, this test should be performed cautiously in patients with suspected adrenal insufficiency because of enhanced susceptibility to hypoglycemia and hypotension. Insulin-induced hypoglycemia is contraindicated in patients with active coronary artery disease or seizure disorders

Hormone production does not always correlate with tumor size. Small hormone-secreting adenomas may cause significant clinical perturbations, whereas larger adenomas that produce less hormone may be clinically silent and remain undiagnosed (if no central compressive effects occur). About one-third of all adenomas are clinically nonfunctioning and produce no distinct clinical hypersecretory syndrome.

Diabetes Mellitus

For example, individuals with type 2 DM may return to the impaired glucose tolerance category with weight loss
These values do not apply to the diagnosis of gestational DM.
It is estimated that between 5 and 10% of individuals who develop DM after age 30 have type 1 DM.
In 2005, the prevalence of DM in the United Sates was estimated to be 0.22% in those <20>20 years. In individuals >60 years, the prevalence of DM was 20.9%. The prevalence is similar in men and women throughout most age ranges (10.5% and 8.8% in individuals >20 years) but is slightly greater in men >60 years
In 2005, the CDC estimated that the prevalence of DM in the United States (age > 20 years) was 13.3% in African Americans, 9.5% in Latinos, 15.1% in Native Americans (American Indians and Alaska natives), and 8.7% in non-Hispanic whites. Individuals belonging to Asian-American or Pacific-Islander ethnic groups in Hawaii are twice as likely to have diabetes compared to non-Hispanic whites.
DM is defined as the level of glycemia at which diabetes-specific complications occur rather than on deviations from a population-based mean
Criterios Dx de DM
• Symptoms of diabetes plus random blood glucose concentration >11.1 mmol/L (200 mg/dL)aor
• Fasting plasma glucose >7.0 mmol/L (126 mg/dL)bor
• Two-hour plasma glucose >11.1 mmol/L (200 mg/dL) during an oral glucose tolerance testc
Glucose tolerance is classified into three categories based on the FPG (Fig. 338-1): (1) FPG <>= 5.6–6.9 mmol/L (100–125 mg/dL) is defined as IFG; and (3) FPG >7.0 mmol/L (126 mg/dL) warrants the diagnosis of DM. Based on the OGTT, IGT is defined as plasma glucose levels between 7.8 and 11.1 mmol/L (140 and 199 mg/dL) and diabetes is defined as a glucose > 11.1 mmol/L (200 mg/dL) 2 h after a 75-g oral glucose load.
Some individuals have both IFG and IGT. Individuals with IFG and/or IGT, recently designated pre-diabetes by the American Diabetes Association (ADA), are at substantial risk for developing type 2 DM (25–40% risk over the next 5 years) and have an increased risk of cardiovascular disease.
The current criteria for the diagnosis of DM emphasize that the FPG is the most reliable and convenient test for identifying DM in asymptomatic individuals. A random plasma glucose concentration >11.1 mmol/L (200 mg/dL) accompanied by classic symptoms of DM (polyuria, polydipsia, weight loss) is sufficient for the diagnosis of DM (Table 338-2). Oral glucose tolerance testing, although still a valid means for diagnosing DM, is not recommended as part of routine care. the A1C is not currently recommended to diagnose diabetes.
Screening: ADA recommends screening all individuals >45 years every 3 years and screening individuals at an earlier age if they are overweight [body mass index (BMI) > 25 km/m2] and have one additional risk factor for diabetes
Risk factors (10)
Family history of diabetes (i.e., parent or sibling with type 2 diabetes)
Obesity (BMI >25 kg/m2) (sobrepeso)
Habitual physical inactivity
Race/ethnicity (e.g., African American, Latino, Native American, Asian American, Pacific Islander)
Previously identified IFG or IGT
History of GDM or delivery of baby >4 kg (>9 lb)
Hypertension (blood pressure >140/90 mmHg)
HDL cholesterol level <35>250 mg/dL (2.82 mmol/L)
Polycystic ovary syndrome or acanthosis nigricans
History of vascular disease

Insuline: Insulin is produced in the beta cells of the pancreatic islets. It is initially synthesized as a single-chain 86-amino-acid precursor polypeptide, preproinsulin. Subsequent proteolytic processing removes the aminoterminal signal peptide, giving rise to proinsulin. Proinsulin is structurally related to insulin-like growth factors I and II, which bind weakly to the insulin receptor. Cleavage of an internal 31-residue fragment from proinsulin generates the C peptide and the A (21 amino acids) and B (30 amino acids) chains of insulin, which are connected by disulfide bonds. The mature insulin molecule and C peptide are stored together and cosecreted from secretory granules in the beta cells. Because the C peptide is cleared more slowly than insulin, it is a useful marker of insulin secretion and allows discrimination of endogenous and exogenous sources of insulin in the evaluation of hypoglycemia

Glut 2 secrecion insulin insulin estimula expression glut 4
Glucose phosphorylation by glucokinase is the rate-limiting step that controls glucose-regulated insulin secretion. Further metabolism of glucose-6-phosphate via glycolysis generates ATP, which inhibits the activity of an ATP-sensitive K+ cannel. Inhibition of this K+ channel induces beta cell membrane depolarization, which opens voltage-dependent calcium channels (leading to an influx of calcium), and stimulates insulin secretion. Glucagon-like peptide 1 (GLP-1), the most potent incretin, is released from L cells in the small intestine and stimulates insulin secretion only when the blood glucose is above the fasting level. Incretin analogues, such as exena-tide, are being used to enhance endogenous insulin secretion.
Once insulin is secreted into the portal venous system, ~50% is degraded by the liver.
Descrito hace más de 40 años, se debe a la acción de 2 hormonas gastrointestinales conocidas como GLP-1 (glucagon-like peptide-1,) y GIP (glucose-dependent insulinotropic polypeptide). GLP-1 es secretado por la células L situadas a nivel del íleon y colon, mientras que GIP es liberado a partir de las células K localizadas en el duodeno y yeyuno. Las incretinas, especialmente el GLP-1, tienen un efecto dual al incrementar la secreción de insulina y suprimir la secreción de glucagón de forma glucosa dependiente. Este efecto se halla presente en la diabetes tipo 2, aunque disminuido. Ambas hormonas, GLP-1 y GIP son inactivadas rápidamente (2-3 min) por la enzima dipeptidil peptidasa-4 (DPP-IV), presente en la circulación (forma soluble) y en diversos tejidos. La infusión iv. continua de GLP-1 disminuye la concentración plasmática de glucosa en ayunas y tras la ingesta.
Para aumentar el efecto de GLP-1 en pacientes con diabetes tipo 2 se han utilizado dos estrategias distintas: (1) utilizar análogos de GLP-1 (incretín-miméticos), como exenatide (Byetta®, comercializado en EEUU) o liraglutide, resistentes a la acción de GLP-1, que se administran 1-2 veces/día por vía sc., o (2) inhibir la enzima DPP-IV para incrementar los niveles de GLP-1 de forma fisiológica (potenciadores del efecto incretina, PEI).
DM1: In the majority, immunologic markers appear after the triggering event but before diabetes becomes clinically overt. Features of diabetes do not become evident until a majority of beta cells are destroyed (~80%. Most individuals with type 1 DM have the HLA DR3 and/or DR4 haplotype. Refinements in genotyping of HLA loci have shown that the haplotypes DQA1*0301, DQB1*0302, and DQB1*0201 are most strongly associated with type 1 DM.
Hence, most individuals with type 1 DM do not have a first-degree relative with this disorder.
Pathologically, the pancreatic islets are infiltrated with lymphocytes (in a process termed insulitis). The islet destruction is mediated by T lymphocytes rather than islet autoantibodies.

Islet cell autoantibodies (ICAs) are a composite of several different antibodies directed at pancreatic islet molecules such as GAD glutamic acid decarboxylase (GAD, the biosynthetic enzyme for the neurotransmitter GABA),, insulin, and IA-2/ICA-512 homology with tyrosine phosphatases )and serve as a marker of the autoimmune process of type 1 DM. ICA’s In combination with impaired insulin secretion after IV glucose tolerance testing, they predict a >50% risk of developing type 1 DM within 5 years.
Putative environmental triggers include viruses (coxsackie and rubella most prominently), bovine milk proteins, and nitrosourea compounds. The Diabetes Prevention Trial—type 1 concluded that administering insulin (IV or PO) to individuals at high risk for developing type 1 DM did not prevent type 1 DM.

DM2: The concordance of type 2 DM in identical twins is between 70 and 90%. As insulin resistance and compensatory hyperinsulinemia progress, the pancreatic islets in certain individuals are unable to sustain the hyperinsulinemic state. IGT, characterized by elevations in postprandial glucose, then develops. A further decline in insulin secretion and an increase in hepatic glucose production lead to overt diabetes with fasting hyperglycemia. Ultimately, beta cell failure may ensue. Insulin resistance impairs glucose utilization by insulin-sensitive tissues and increases hepatic glucose output; both effects contribute to the hyperglycemia. Increased hepatic glucose output predominantly accounts for increased FPG levels, whereas decreased peripheral glucose usage results in postprandial hyperglycemia. For example, adipocytes secrete a number of biologic products (nonesterified free fatty acids, retinol-binding protein 4, leptin, TNF-, resistin, and adiponectin). In addition to regulating body weight, appetite, and energy expenditure, adipokines also modulate insulin sensitivity. The increased production of free fatty acids and some adipokines may cause insulin resistance in skeletal muscle and liver
This lipid storage or steatosis in the liver may lead to nonalcoholic fatty liver disease (Chap. 303) and abnormal liver function tests. This is also responsible for the dyslipidemia found in type 2 DM [elevated triglycerides, reduced high-density lipoprotein (HDL), and increased small dense low-density lipoprotein (LDL) particles

Metabolic syndrome: Two distinct syndromes of severe insulin resistance have been described in adults: (1) type A, which affects young women and is characterized by severe hyperinsulinemia, obesity, and features of hyperandrogenism; and (2) type B, which affects middle-aged women and is characterized by severe hyperinsulinemia, features of hyperandrogenism, and autoimmune disorders

demonstrated that intensive changes in lifestyle (diet and exercise for 30 min/day five times/week) in individuals with IGT prevented or delayed the development of type 2 DM by 58% compared to placebo. metformin prevented or delayed diabetes by 31% compared to placebo. acarbose, metformin, thiazolidinediones, and orlistat prevent or delay type 2 DM but are not approved for this purpose. A recent ADA Consensus panel concluded that metformin, but not other medications, could be considered in individuals with both IFG and IGT who are at very high risk for progression to diabetes.

Six different variants of MODY, caused by mutations in genes encoding islet-enriched transcription factors or glucokinase (Fig. 338-4), are transmitted as autosomal dominant disorders. MODY 1, MODY 3, and MODY 5 are caused by mutations in the hepatocyte nuclear transcription factor (HNF) 4, HNF-1, and HNF-1, respectively. Studies of populations with type 2 DM suggest that mutations in MODY-associated genes are rare (<5%) causes of type 2 DM