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44 Kung, A.W. et al. (1995) Elevated serum lipoprotein(a) in subclinical hypothyroidism. Clin. Endocrinol. 43, 445–449 45 Hickie, I. et al. (1996) Clinical and subclinical hypothyroidism in patients with chronic and treatment-resistant depression. Aust. New Zealand J. Psychiatry 30, 246–252 46 Baldini, I.M. et al. (1997) Psychopathological and cognitive features in subclinical hypothyroidism. Prog. Neuropsychopharmacol. Biol. Psychiatry 21, 925–935 47 Jaeschke, R. et al. (1996) Does treatment with L-thyroxine influence health status in middleaged and older adults with subclinical hypothyroidism? J. Gen. Intern. Med. 11, 744–749 48 Yildirimkaya, M. et al. (1996) Lipoprotein (a) concentration in subclinical hypothyroidism before and after levo-thyroxine therapy. Endocr. J. 43, 731–736 49 Tanis, B.C. et al. (1996) Effect of thyroid substitution on hypercholesterolaemia in patients with subclinical hypothyroidism: a reanalysis of intervention studies. Clin. Endocrinol. 44, 643–649 50 Ayala, A.R. and Wartofsky, L. (1997) Minimally symptomatic (subclinical) hypothyroidism. The Endocrinologist 7, 44–50 51 Rose, S.R. (1995) Isolated central hypothyroidism in short stature. Pediatr. Res. 38, 967–973 52 Pitukcheewanont, P. and Rose, S.R. (1997) Nocturnal TSH surge: a sensitive diagnostic test

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54

55

56

57

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for central hypothyroidism in children. The Endocrinologist 7, 226–232 Lam, K.S. et al. (1991) Effects of cranial irradiation on hypothalamic–pituitary function – a 5-year longitudinal study in patients with nasopharyngeal carcinoma. Q. J. Med. 78, 165–176 Littley, M.D. et al. (1989) Radiation-induced hypopituitarism is dose-dependent. Clin. Endocrinol. 31, 363–373 Sklar, C.A. and Constine, L.S. (1995) Chronic neuroendocrinological sequelae of radiation therapy. Int. J. Radiat. Oncol. Biol. Phys. 31, 1113–1121 Maccagnan, P. et al. (1999) Abnormal circadian rhythm and increased non-pulsatile secretion of thyrotrophin in Sheehan’s syndrome. Clin. Endocrinol. 51, 439–447 Devney, R.B. et al. (1984) Serial thyroid function measurements in children with Hodgkin disease. J. Pediatr. 105, 223–227 Ogilvy-Stuart, A.L. et al. (1992) Endocrine deficit after fractionated total body irradiation. Arch. Dis. Child. 67, 1107–1110 Chen, M.S. et al. (1989) Prospective hormone study of hypothalamic–pituitary function in patients with nasopharyngeal carcinoma after high dose irradiation. Jpn. J. Clin. Oncol. 19, 265–270 Tell, R. et al. (1997) Hypothyroidism after external radiotherapy for head and neck

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62

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cancer. Int. Radiat. Oncol. Biol. Phys. 39, 303–308 Michel, G. et al. (1997) Late effects of allogeneic bone marrow transplantation for children with acute myeloblastic leukemia in first complete remission: the impact of conditioning regimen without total-body irradiation – a report from the Socié té Française de Greffe de Moelle. J. Clin. Oncol. 15, 2238–2246 DeGroot, L.J. (1999) Dangerous dogmas in medicine: the nonthyroidal illness syndrome. J. Clin. Endocrinol. Metab. 84, 151–164 Van Blerk, M. et al. (1996) Four radioisotopic immunoassays of free thyroxine compared. Ann. Clin. Biochem. 33, 335–343 Christenson, R.H. et al. (1995) Thyroid function testing evaluated on three immunoassay systems. J. Clin. Lab. Anal. 9, 178–183 Sapin, R. et al. (1996) Familial dysalbuminemic hyperthyroxinemia and thyroid hormone autoantibodies: interference in current free thyroid hormone assays. Horm. Res. 45, 139–141 Faix, J.D. et al. (1995) Indirect estimation of thyroid hormone-binding proteins to calculate free thyroxine index: comparison of nonisotopic methods that use labeled thyroxine (‘T-uptake’). Clin. Chem. 41, 41–47 Ferretti, E. et al. (1999) Evaluation of the adequacy of levothyroxine replacement therapy in patients with central hypothyroidism. J. Clin. Endocrinol. Metab. 84, 924–929

Apparent mineralocorticoid excess Robert C. Wilson, Saroj Nimkarn and Maria I. New Apparent mineralocorticoid excess (AME) is a potentially fatal genetic disorder causing severe juvenile hypertension, pre- and postnatal growth failure, hypokalemia and low to undetectable levels of renin and aldosterone. It is caused by autosomal recessive mutations in the HSD11B2 gene, which result in β-hydroxysteroid dehydrogenase type 2 (11β β-HSD2). The a deficiency of 11β β-HSD2 enzyme is responsible for the conversion of cortisol to the inactive 11β metabolite cortisone and, therefore, protects the mineralocorticoid receptors from cortisol intoxication. In 1998, a mild form of this disease was reported, which might represent an important cause of low-renin hypertension. Early and vigilant treatment might prevent or improve the morbidity and mortality of end-organ damage.

Robert C. Wilson Saroj Nimkarn Maria I. New* Pediatric Endocrinology, New York-Presbyterian Hospital and the Weill Medical College of Cornell University, 525 East 68th Street, New York, NY 10021, USA. *e-mail: minew@ mail.med.cornell.edu

Apparent mineralocorticoid excess (AME) is a genetic disorder that typically causes severe hypertension in children, pre- and postnatal growth failure, hypokalemic metabolic alkalosis and low to undetectable levels of renin and aldosterone. This potentially fatal disease is the result of autosomal recessive mutations in the HSD11B2 gene, which cause a deficiency of 11β-hydroxysteroid dehydrogenase (11β-HSD) type 2. Investigations into the cause of this disease have shown that the activity of aldosterone in mineralocorticoid-responsive cells depends on the function of a metabolic enzyme rather

than on the specificity of aldosterone for the mineralocorticoid receptor (MR). AME also has broader significance because of the possible link between 11β-HSD activity and common essential hypertension, as well as a clearer understanding of human hormone action. Historical background

Although Werder et al.1 described a patient with similar clinical features to AME in 1974, the first biochemical description of this disease was in a threeyear-old Native American child from the Zuni tribe2. Detailed clinical and endocrine evaluations of this child established the presence of features that could not be explained by a known syndrome. Aldosterone regulates electrolyte excretion and intravascular volume by stimulating increased resorption of Na+ from the urine. It is the most potent endogenous mineralocorticoid; yet, despite strong evidence of mineralocorticoid excess and hyperaldosteronism, aldosterone was undetectable in both the prismatic case and similar cases that were subsequently identified. Thus, it was initially thought that the condition was caused by an unknown

http://tem.trends.com 1043-2760/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S1043-2760(00)00356-8

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mineralocorticoid2,3; however, attempts to identify such a factor were unsuccessful. With the use of tritiated cortisol, it was found that the metabolism of cortisol to biologically inactive cortisone was decreased and that the serum cortisol half-life was prolonged in these cases, whereas the conversion of cortisone to cortisol was normal4. This implied that 11β-HSD, the enzyme that converts cortisol to cortisone, might be deficient. It was also postulated that the specificity of the MR was lost in these patients, enabling cortisol to bind to the MR and act as a mineralocorticoid4–6. Several studies demonstrated that the MR has equal affinity for aldosterone and cortisol in vitro; however, in vivo the MR clearly favors the binding of aldosterone7–10. Because normal circulating levels of cortisol are 100to 1000-fold higher than those of aldosterone, it appeared that when specificity was lost endogenous exposure of the MR to such high levels of cortisol resulted in the binding of this molecule, rather than aldosterone, to the MR. In 1982, it was proposed that cortisol was the mineralocorticoid that induced hypertension5. Biochemical findings were in agreement with this theory because in patients with AME, hydrocortisone treatment aggravated hypertension and hypokalemia5,6. The role that 11β-HSD plays in MR specificity was first established by studying the effects of the drug carbenoxolone and extracts from the root of the licorice plant, Glycyrrhiza glabra. Licorice ingestion in large amounts can cause Na+ retention, raised blood pressure and K+ wasting, resulting in a hypertensive state resembling AME (Ref. 11). Glycyrrhetinic acid, the hydrolytic derivative of the active agent in licorice extracts, was found to be a competitive inhibitor of 11β-HSD (Ref. 12). Carbenoxolone, the semisynthetic analog of glycyrrhetinic acid, can also induce AME-like side effects, including Na+ retention, hypokalemic alkalosis, low levels of plasma renin and hypertension13. In addition, there is a pronounced increase in the urinary metabolite ratio of cortisol to cortisone in humans treated with carbenoxolone and in AME patients, supporting the hypothesis of abnormal 11β-hydroxysteroid dehydrogenation4. Because defective 11β-HSD appeared to be the likely candidate for the cause of AME, researchers sought to isolate both the cDNA encoding the enzyme and the protein itself. This search first led to the discovery of 11β-HSD1, or hepatic 11β-HSD (Refs 14,15). The identification of the NADPdependent 11β-HSD1 was made in rat liver homogenates. However, subsequent studies on 11β-HSD1 found that it was present primarily in the liver, gonads, lung, decidua, pituitary and cerebellum, where there is little mineralocorticoid activity15,16. The enzyme 11β-HSD1 also favors oxoreductase activity, which serves to reactivate cortisone to cortisol. In addition, no mutations in the human gene encoding 11β-HSD1 were found in AME patients, http://tem.trends.com

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suggesting the presence of another 11β-HSD isoform17. Because aldosterone acts primarily through its effects on the renal distal convoluted tubules and cortical collecting ducts, it was predicted that both the HSD isozyme and the MR should exist in these locations. The activity of a separate NAD-dependent isoform (type 2) in the distal nephron was identified in the rabbit kidney18 and, in 1994, the cDNA encoding 11β-HSD2 (HSD11B2) was isolated and cloned with the use of expression studies in kidney cells of sheep, humans and rabbits16,19,20. This isozyme possessed all of the properties necessary for protecting the MR: a very high affinity for endogenous glucocorticoids, a high abundance in target cells and unidirectional dehydrogenase activity. Later studies found that human HSD11B2 mRNA was expressed in the kidney cortex and medulla, the sigmoid and rectal colon, and in the salivary gland21, pancreas, prostate, ovary, small intestine, placenta, spleen and testes16. The presence of both 11β-HSD2 and MRs has also been detected in fetal skin, the upper gastrointestinal tract and lung22. With the use of in situ hybridization and immunohistochemistry, human 11β-HSD2 expression was localized to the distal tubule, and the HSD11B2 gene was mapped to chromosome 16q22 (Refs 23,24). HSD11B2 is approximately 6 kb in length and contains five exons24. The Km of 11β-HSD2 with cortisol as a substrate is 54 nM in the human placenta25 and 35 nM in the human colon26, indicating that 11β-HSD2 has a significantly higher affinity for cortisol than does 11β-HSD1. These data revealed that a defect in the type 2 isoform is probably responsible for AME (Refs 20,27–29). Indeed, the two 11β-HSD isoforms have only ~20% sequence homology, suggesting that the isozymes belong to different gene families15,16. In 1995, Wilson et al. identified the first mutation in the HSD11B2 gene in a consanguineous Iranian family with three siblings suffering from AME (a C to T transition resulting in the R337C mutation)30. Eighteen mutations have since been identified in the HSD11B2 gene in patients affected with AME, most of which completely abolish the activity of 11β-HSD2 (Table 1)27–35. Epidemiology

AME is rare, having been identified in only approximately 60 patients worldwide in the past 20 years. To date, most patients with AME who have undergone molecular genetic analysis have been homozygous for one of the different mutations. Rare autosomal recessive mutations are classically explained by consanguinity, endogamy (a high coefficient of inbreeding) or a founder effect. In a 1995 study of eight families with members affected by AME, seven of the families appeared to conform with one of these three explanations32. Four families came from ancestry where consanguinity and tribal inbreeding

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R279C A238V R208H

R213C

R208C

R337H,∆Y338 R337C

P227L

R374X

D244N Sac I

Sac I

∼3 kb I

II

III

IV

V

C to T

G305,∆11nt Y232,∆9nt

R186C L250P, L251S L250R

E286-1 frameshift E356-1 frameshift TRENDS in Endocrinology & Metabolism

Fig. 1. Mutations in the gene encoding 11β-hydroxysteroid dehydrogenase type 2 in patients with apparent mineralocorticoid excess (see Table 1 for references). The HSD11B2 gene has five exons (I–V), is 6.2 kb long, and has been mapped to chromosome 16q22. All affected patients are homozygous mutants except for two patients, who are compound heterozygotes (D244N/L250R and Y232,∆9nt/G305,∆11nt).

were the custom, and three came from a Zoroastrian population that originated in Iran and was subsequently driven out by Muslims in the 7th century. In the remaining family, African Americans from North Carolina, consanguinity was not proved. Only two compound heterozygous patients with severe AME have been identified (Refs 28,33). Clinical and biochemical features

AME usually presents early in life with clinical features including low birth weight, severe hypertension, failure to thrive and persistent polydipsia and polyuria. Biochemical profiles demonstrate metabolic alkalosis and severe hypokalemia and hypoaldosteronemia. Plasma renin activity (PRA) is suppressed, suggesting volumeexpansion hypertension, which responds to dietary Na+ restriction. Biochemical diagnosis of AME can be made by measuring the ratio of urinary cortisol metabolites to cortisone, often measured as an increase in the sum of the urinary tetrahydrocortisol (THF) and allotetrahydrocortisol, divided by the concentration of tetrahydrocortisone (THE) [(THF + 5αΤΗF)/THE]. In a report of 14 AME patients, urinary metabolites of cortisol demonstrated an abnormal ratio of THF:THE, with a predominance of THF (Ref. 33). The ratio of [(THF + 5αΤΗF)/THE] was 6.7 to 33.0, whereas the normal ratio is 1.0. The optimal diagnostic test is to measure the generation of tritiated water in urine samples when 11-tritiated cortisol is injected, as described by Hellman et al.36 Infusion of 11-tritiated cortisol in patients revealed the conversion of cortisol to cortisone to be 0–6% in typical AME patients, whereas the normal conversion is 90–95%. In addition, an assay that distinguishes http://tem.trends.com

between 5α- and 5β-tetrahydrometabolites can demonstrate that 5β-reductase activity is reduced or inhibited in AME (Refs 37,38). Another biochemical finding was that of low cortisol secretion rates despite normal serum cortisol concentrations. This discrepancy is probably the result of the greatly increased half-life of cortisol. Patients have a normal response to adrenocorticotropin stimulation tests. AME patients worldwide exhibit characteristic signs of a severe 11β-HSD2 defect1,2,4,17,30,33,37,39–51. Birth weights of AME babies are lower than those of their unaffected siblings, and the patients are short, underweight and hypertensive compared with age-matched controls. Severe hypertension and hypokalemic alkalosis are associated with end organ damage in AME patients, particularly of the retina, kidney, cardiovascular system and central nervous system (CNS). Cardiac damage is manifested mainly in the form of concentric left ventricular hypertrophy with increased left ventricular mass. Renal manifestations are seen in the form of nephrocalcinosis and, in some cases, renal insufficiency. Hypercalciuria is also seen, although the mechanism for this finding is unclear. Hypertensive retinopathy is consistently found, and ranges from mild to moderate grades. CNS involvement in these patients ranged from developmental delay to various electroencephalograph abnormalities, seizure disorders and generalized cerebral dysfunction. This is a particularly important observation in light of the emerging roles for mineralocorticoids in the CNS (Refs 52–54). A deficiency of 11β-HSD2 in the fetal placental unit might lead to intra-uterine growth retardation and low birth weight, as demonstrated by the low birth weight of AME patients33. It has been reported that there is a positive correlation between normal placental 11β-HSD2 activity and birth weight55. The low birth weight consistently noted in AME patients has been attributed to a deficiency of placental 11β-HSD2, causing transplacental passage of cortisol to the fetus46,56–58. However, this hypothesis requires further investigation because, in a large study of pregnant women who carried fetuses with 21-hydroxylase deficiency congenital adrenal hyperplasia, and who were treated with dexamethasone (a potent glucocorticoid), the women gave birth to infants of normal birth weight59–62. Accordingly, dexamethasone, which passes to the fetus, does not appear to cause low birth weight. Variants of AME

Until 1998, when an unusual patient with a mild form of AME was reported by Wilson et al.34, all patients with AME had the characteristic phenotype of a severe 11β-HSD2 defect. Asymptomatic, mild, lowrenin hypertension was diagnosed in an American girl at age 12.5 years during a sports physical in 1995. Further analysis revealed normal serum electrolytes,

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but mild hypoaldosteronemia and undetectable plasma renin. This patient exhibited only a moderately abnormal ratio of cortisol to cortisone metabolites: [(THF + 5αTHF)/THE was 3.0]. Metabolism of cortisol to cortisone, as determined by the measurement of tritiated water release after 11-tritiated cortisol infusion, was 58%, compared with <6% in typical AME patients (Table 1). The parents of this atypical patient are consanguineous Mennonites of Prussian descent (Alexanderwohl church) (Fig. 2), and the only family member with hypertension is the maternal grandmother. Although the patient had low renin, she lacked hypokalemia, low birth weight and had only mild hypertension. A diagnosis of AME was established on the basis of biochemical evidence and mutational analysis, that revealed a homozygous mutation (P227L) in the HSD11B2 gene. Kinetic analysis of the 11β-HSD2 enzyme in this patient showed a Km for cortisol inbetween the values for severe AME patients and unaffected individuals34. A previous study of a severe AME patient had demonstrated a Km of 1010 nM, compared with the normal control value of 110 nM (Refs 63,64). In vitro analysis of the P227L mutation in the patient with mild AME gave a Km for cortisol of 300 nM, suggesting a less severe defect than in other patients, resulting in her mild phenotype. The Mennonite community (2000 individuals) to which our patient belonged was studied to determine the heterozygote frequency of the P227L mutation65. DNA samples from 445 people were analyzed and a heterozygote frequency of 3.0% was revealed. Considering that there are only ~50 patients known worldwide with AME, this frequency is very high. Another variant of AME (previously known as ‘type II’) has been reported in five individuals in whom the urinary (THF + 5αTHF)/THE ratio was less raised than in patients with classic AME, but the phenotype was essentially the same as in the more severe cases35,66–69. Four of these individuals belong to a Sardinian pedigree and have partial reduction of 11β-HSD2 activity owing to a homozygous point mutation (R279C) in HSD11B2. Thirteen other family members were heterozygous for the R279C amino acid substitution and found to have subtle defects in their cortisol metabolism, although they were phenotypically normal35. Treatment

The treatment of AME is primarily aimed at correcting hypokalemia and hypertension. Spironolactone, an MR receptor antagonist, is the accepted medication of choice. In addition to spironolactone, other medications can also be used, such as the K+-conserving diuretic amiloride, the adrenergic blocking agent atenolol and the ACE inhibitor enalapril. Because of the difficulty of dose titration in children that resulted in one patient going into shock, triamterene should be avoided. A reduction in dietary Na+ and supplemental K+ intake http://tem.trends.com

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has also been shown to have a beneficial effect. In our experience, and that of others, glucocorticoids of all types will aggravate AME (Ref. 6). It was reported previously that hydrocortisone administration raised the blood pressure and lowered the serum K+ concentration in patients with AME (Refs 2,6). In two additional patients, hydrocortisone administration increased the mean 24-h blood pressure and lowered the serum K+ significantly, in spite of spironolactone treatment33. Follow up studies of 14 AME patients from the New York Presbyterian Hospital-Weill Medical College of Cornell have been reported33. These patients were treated with spironolactone and demonstrated improvements in their clinical symptoms. The dose range of spironolactone was wide (2–10 mg kg−1 day−1) because it was started at a very low level and gradually increased until the desired blood pressure response and serum K+ concentration were achieved. Because hypercalciuria and nephrocalcinosis are consistent features of this disease, a thiazide diuretic was added in most of our patients’ treatment regimens after years of treatment with spironolactone. The reversal of bilateral nephrocalcinosis of the kidneys in patients is evidence of the success of treatment. Thiazide diuretics also help to lower blood pressure and, in some patients, might enable the dose of spironolactone to be reduced. This is particularly important in patients manifesting anti-androgenic side effects (e.g. gynecomastia) of spironolactone. In one patient who was poorly compliant with the prescribed low-salt diet, the use of low-dose furosemide to control the excess Na+, in addition to spironolactone and K+ supplementation, proved to be beneficial for blood pressure control. However, loop diuretics must be carefully administered, because they can aggravate hypokalemia and alkalosis. Improved growth and the reversal of hypertensive retinopathy and left ventricular hypertrophy in some patients further demonstrates that proper treatment and meticulous compliance can control this disease33. In a recently reported case, kidney transplantation cured AME (Ref. 70). The patient had been hypertensive from age 19, and from AME diagnosis at age 28 she was successfully treated with atenolol, enalapril and dexamethasone. At age 31 she developed endstage renal failure and underwent kidney transplantation; her own kidneys were left intact. Serum K+, PRA and blood pressure were consistently normalized, probably as a result of the synthesis of active 11β-HSD2 by the new kidney. In addition, the urinary ratio of cortisol to cortisone also improved. In a review of AME and suspected AME patients in the worldwide literature, five died of AME-related illnesses, and two diagnosed genetically were stillborn34. In some cases, early and vigilant treatment of AME patients can prevent or improve the morbidity and mortality of end-organ damage, such as renal or cardiovascular damage and

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Table 1. Review of AME patients worldwide: signs and biochemical features at presentation, and subsequent biochemical and genetic evaluationa Patient

Kindred

Country of origin, Age Sex Birth BP BP (90th Serum Kⴙ THFⴙ F secretion ethnicity, religious (years) weight (mm Hg) centile (mmol lⴚ1) 5␣THF/ rate group (kg) for age) THE (mg dayⴚ1)

% HSD11␤2 Conversion mutation →E F→

Refs

1b

1

2 3 4 5 6 7 8

2 3 4 4 5 6 7

9

7

10

8

11 12 13 14 15

9 9 9 10 11

16 17

12 13

18

13

19b

13

20

14

21

15

22

16

23

17

American Indian (Zuni tribe) Iran (Zoroastrian) Italy/Morocco African American African American Northern India Northern India Oman (Mozaini tribe) Oman (Mozaini tribe) American Indian (Chippewa tribe) Iran Iran Iran Turkey North America (Mennonite) American Indian South American Indian/Caucasian South American Indian/Caucasian South American Indian/Caucasian American Indian/ Caucasian Europe/ American Indian Mexico/ North America Ireland/America

24 25 26b,c 27b,c 28 29 30 31 32b 33 34 35b 36 37 38b 39 40 41 42f 43f 44f 45

18 18 18 18 19 20 21 22 23 24 25 26 27 28 18 29 30 30 31 32 33 34

46g 47g 48g 49g Normal values

35 35 35 35

Asia/Pakistan Asia/Pakistan Asia/Pakistan Asia/Pakistan Japan Brazil Germany France American Indian Caucasian Northern Europe Caucasian Caucasian Caucasian Asia/Pakistan Turkey France France

Argentina (Caucasian) Sardinia Sardinia Sardinia Sardinia

1.0

Fe

1.8

180/140

105/69

2.2

32.10

0.08

0.0

E356-1 frameshift

32

9.0 4.0 9.3 4.3 0.8 2.5 10.9

M M Fe Fe M M M

2.0 2.3 2.1 2.6 2.0 2.3 2.1

250/180 160/110 130/90 142/98 150/100 150/100 170/110

110/71 104/67 109/71 98/70 105/67 91/68 115/73

3.5 3.1 2.7 2.8 2.4 1.8 1.7

9.10d 33.00 8.90 14.90 20.10 12.50 27.90

0.47 0.72 0.12 0.15 0.05 0.83 0.36

0.0 ND 2.0 4.2 6.0 2.0 ND

R337H,∆Y338 L250R/D244N R186C R186C R337H,∆Y338 R337H,∆Y338 R208C

32 33 32 32 32 32 32

9.3

M

2.4

160/118

110/71

2.9

27.30

0.24

ND

R208C

32

3.3

M

2.0

205/130

99/60

0.9

26.80

0.51

1.5

L250P, L251S

32

14.0 11.6 4.0 0.1 12.6

Fe M Fe M Fe

2.2 2.1 2.4 2.5 3.6

220/160 170/110 160/100 155/115 160/90

116/79 110/72 98/70 99/60 110/72

2.8 2.0 3.1 3.0 5.0

8.91 6.85 6.70 13.80 3.00

ND ND ND ND 0.55

ND ND ND 4.5 58.4

R337C R337C R337C N286-1 frameshift P227L

30 30 30 33 34

9.0 3.0

M Fe

170/100 170/110

110/71 99/71

2.3

14.40 31.30

R208C R213C

31 31,39

3.8

Fe

200/120

108/70

2.0

13.40

R213C

31,39

6.0

M

ND

39

1.0

Fe

142/92

105/69

–

73.80

L250P, L251S

31

1.6

M

140/100

105/69

3.1

19.80

L250P, L251S

31,50

26.0

Fe

180/120

123/88

–

7.90

Intron 3 (C to T)

31

2.3

M

149/83

91/68

–

134.00

31

3.5 1.4 – – 2.0 7.0 3.0 4.0 2.7 2.0 1.6 0.4 0.8 21.0 3.5 1.3 2.0 3.3 3.3 3.5 9.0 11.0

M M M M M Fe Fe Fe Fe M M M Fe M M M M M

141/117 144/91 – – 160/90 160/120 175/110 140/60 180/120 110/65 150/110 200/100 140/100 200/145

2.1 3.0 – – 2.7 1.8 2.8 2.0 2.7 2.2 2.6 1.8 3.2 1.7 Low Low 2.5 2.9

20.00 50.00 – – 43.70 29.80 ND 0.61d 9.78 15.87 45.00 68.80 15.00d 13.60 ND 38.06 22.00 42.00

Codon 232,∆9nt/ Codon 305,∆11nt R374X R374X R374X R374X R208H/R337H,∆Y338 A328V ND ND ND ND ND ND R374Xe ND ND ND ND ND ND ND ND R213C

27,46 27,46 27,46 27,46 28 29,41 1 43 50 44 48 45 49 40 27,46 47 51 51 42 42 42 80

28.0 32.0 33.0 32.0

Fe Fe M Fe

R279C R279C R279C R279C

35,70,81 35,81 35,66 35,66

M

–

Low 3.1 3.4

120/90 140/80 160/100

100/70 105/69 – – 91/68 110/73 99/71 98/70 101/71 91/68 105/69 105/69 120/80 121/81 – 105/69 91/68 99/60

2.1

130/90

114/74

2.8

10.40

160/110 150/110 180/140 175/135

140/90 140/90 140/90 140/90

2.6h 2.9h 1.8h 2.1h 3.2–5.2

4.20 1.90 4.53 3.19 1.00

– – 2.5

2.1

2.2 2.4

>2.5

aAbbreviations:

– –

– –

1.00

8.00 0.0

0.0

11.50

90.0–95.0

AME, apparent mineralocorticoid excess; BP, blood pressure; E, cortisone; F, cortisol; Fe, female; HSD, hydroxysteroid dehydrogenase; M, male; ND, not determined; THE, tetrahydrocortisone; THF, tetrahydrocortisol. bDied. Patient 19 died of stroke and might have been affected by AME. Patients 26 and 27 were stillborn. Patient 35 died after fever, persistently raised blood pressure and hypokalemia. Patient 38, twin of Patient 24, died of a diarrheal illness; AME is suspected. cPlacental DNA. dTHF/THE. eP.M. Stewart, pers. commun. fUnreported potential AME patients. gAlthough symptomatic, these patients were previously categorized as ‘type II’ AME patients owing to their moderate THF 5␣THF/THE ratios. hPlasma K⫹.

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Prussian

Alexanderwohl

I 2

1 II 1

2

3

4

5

6

8

7

14

10 11 12 13

9

III 1

2

5

4

3

8

7

6

IV 2

1

4

3

V 1

2

VI 1

2

3 TRENDS in Endocrinology & Metabolism

Fig. 2. Pedigree of Mennonite family showing consanguinity79.

retinopathy. Studying the outcome of therapy in more patients might help to establish the optimal treatment. AME and essential hypertension

Acknowledgements Significant sections of this work were supported by USPHS Grant HD00072 and General Clinical Research Center Grant RR 06020. We wish to thank Laurie Vandermolen and Andrea Putnam for their editorial assistance in the preparation of this manuscript.

Essential hypertension has been estimated to occur in 15 million residents of the USA, and ~40% of these cases are associated with low renin. Several studies provide evidence that reduced 11β-HSD2 activity might be a factor in a subset of patients diagnosed with essential hypertension71,72. Studies by Walker et al. have shown an increase in the cortisol metabolite 5α-THF in hypertensive patients whose parents also had high blood pressure73, in addition to an increased cortisol half-life and increased vasoconstrictor sensitivity to glucocorticoids in patients with essential hypertension74. Although salt sensitivity can occur in normotensive individuals, it is also a characteristic of

References 1 Werder, E.A. et al. (1974) Unusual steroid excretion in a child with low-renin hypertension. Res. Steroids 6, 385–389 2 New, M.I. et al. (1977) Evidence for an unidentified steroid in a child with apparent mineralocorticoid hypertension. J. Clin. Endocrinol. Metab. 44, 924–933 3 Ulick, S. et al. (1977) An abnormality in steroid reductive metabolism in a hypertensive syndrome. J. Clin. Endocrinol. Metab. 44, 799–802 4 Ulick, S. et al. (1979) A syndrome of apparent mineralocorticoid excess associated with defects in the peripheral metabolism of cortisol. J. Clin. Endocrinol. Metab. 49, 757–764 5 New, M.I. et al. (1982) A genetic defect in cortisol metabolism as the basis for the syndrome of apparent mineralocorticoid excess. In Endocrinology of Hypertension, Serono Symposia No. 50 (Mantero, F. et al., eds), pp. 85–101, Academic Press 6 Oberfield, S.E. et al. (1983) Metabolic and blood pressure responses to hydrocortisone in the syndrome of apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab. 56, 332–339 http://tem.trends.com

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patients with low-renin hypertension75,76. Furthermore, it is probable that decreased 11β-HSD2 activity might cause the salt sensitivity seen in some hypertensives. Lovati et al. have shown a positive association between a polymorphic microsatellite marker near the HSD11B2 gene and reduced 11β-HSD2 activity in Caucasian saltsensitive men77. In addition, an association between a microsatellite marker near the HSD11B2 gene and African Americans with a salt-dependent hypertensive endstage renal disease has been demonstrated78. These data suggest a contribution of variants of the HSD11B2 gene to enhanced blood pressure responses to salt. However, a recent report comparing hypertensive patients with their siblings and with controls found no correlation between variants of the HSD11B2 gene and their contribution to essential hypertension susceptibility38, and the authors concluded that variants do not contribute substantially to essential hypertension in Caucasians. However, low-renin hypertension, which can appear in a very mild form, was not analyzed separately. Consequently, it might be found that mild mutations in the HSD11B2 gene are an unrecognized cause of low-renin hypertension. Although AME is rare, mild defects in 11β-HSD2 might occur more frequently in the general population and present with a wide spectrum of clinical findings. Therefore, AME should be considered as a potential cause in hypertensive children, especially because treatment with spironolactone results in prompt remission of symptoms. The elucidation of the etiology of AME not only revealed a possible link between essential hypertension and 11β-HSD2 activity, but also opened up a new field of receptor biology by demonstrating that specificity for the MR is conferred by an enzyme.

7 Marver, D. et al. (1974) Renal aldosterone receptors: studies with (3H)aldosterone and the anti-mineralocorticoid (3H)spirolactone (SC-26304). Proc. Natl. Acad. Sci. U. S. A. 71, 1431–1435 8 Krozowski, Z.S. and Funder, J.W. (1983) Renal mineralocorticoid receptors and hippocampal corticosterone-binding species have identical intrinsic steroid specificity. Proc. Natl. Acad. Sci. U. S. A. 80, 6056–6060 9 Arriza, J.L. et al. (1987) Cloning of human mineralocorticoid receptor complementary DNA: structural and functional kinship with the glucocorticoid receptor. Science 237, 268–275 10 Funder, J.W. et al. (1988) Mineralocorticoid action: target tissue specificity is enzyme, not receptor, mediated. Science 242, 583–585 11 Stewart, P.M. et al. (1987) Mineralocorticoid activity of liquorice: 11-β-hydroxysteroid dehydrogenase deficiency comes of age. Lancet ii, 821–824 12 Farese, R.V., Jr et al. (1991) Licorice-induced hypermineralocorticoidism. New Engl. J. Med. 325, 1223–1227 13 Stewart, P.M. et al. (1990) Mineralocorticoid activity of carbenoxolone: contrasting effects of

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15

16

17

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carbenoxolone and liquorice on 11 β-hydroxysteroid dehydrogenase activity in man. Clin. Sci. 78, 49–54 Lakshmi, V. and Monder, C. (1988) Purification and characterization of the corticosteroid 11 betadehydrogenase component of the rat liver 11 β-hydroxysteroid dehydrogenase complex. Endocrinology 123, 2390–2398 Tannin, G.M. et al. (1991) The human gene for 11 β-hydroxysteroid dehydrogenase. Structure, tissue distribution, and chromosomal localization. J. Biol. Chem. 266, 16653–16658 Albiston, A.L. et al. (1994) Cloning and tissue distribution of the human 11 β-hydroxysteroid dehydrogenase type 2 enzyme. Mol. Cell. Endocrinol. 105, R11–R17 Nikkila, H. et al. (1993) Defects in the HSD11 gene encoding 11 β-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency. J. Clin. Endocrinol. Metab. 77, 687–691 Rusvai, E. and Naray-Fejes-Toth, A. (1993) A new isoform of 11 β-hydroxysteroid dehydrogenase in aldosterone target cells. J. Biol. Chem. 268, 10717–10720

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Review

19 Agarwal, A.K. et al. (1994) NAD(+)-dependent isoform of 11 β-hydroxysteroid dehydrogenase. Cloning and characterization of cDNA from sheep kidney. J. Biol. Chem. 269, 25959–25962 20 Naray-Fejes-Toth, A. and Fejes-Toth, G. (1995) Expression cloning of the aldosterone target cellspecific 11 β-hydroxysteroid dehydrogenase from rabbit collecting duct cells. Endocrinology 136, 2579–2586 21 Whorwood, C.B. et al. (1995) Detection of human 11β-hydroxysteroid dehydrogenase isoforms using reverse-transcriptase–polymerase chain reaction and localization of the type 2 isoform in renal collecting ducts. Mol. Cell. Endocrinol. 110, R7–R11 22 White, P.C. et al. (1997) 11 β-Hydroxysteroid dehydrogenase and the syndrome of apparent mineralocorticoid excess. Endocr. Rev. 18, 135–156 23 Krozowski, Z.S. et al. (1995) Localization of the gene for human 11β-hydroxysteroid dehydrogenase type 2 enzyme to chromosome 16q22. Cytogenet. Cell Genet. 71, 124–125 24 Agarwal, A.K. et al. (1995) Gene structure and chromosomal localization of the human HSD11K gene encoding the kidney (type 2) isozyme of 11β-hydroxysteroid dehydrogenase. Genomics 29, 195–199 25 Brown, R.W. et al. (1993) Human placental 11 β-hydroxysteroid dehydrogenase: evidence for and partial purification of a distinct NAD-dependent isoform. Endocrinology 132, 2614–2621 26 Whorwood, C.B. et al. (1994) Epithelial cell localization of type 2 11 β-hydroxysteroid dehydrogenase in rat and human colon. Endocrinology 135, 2533–2541 27 Stewart, P.M. et al. (1996) Hypertension in the syndrome of apparent mineralocorticoid excess due to mutation of the 11β-hydroxysteroid dehydrogenase type 2 gene. Lancet 347, 88–91 28 Kitanaka, S. et al. (1997) A new compound heterozygous mutation in the 11β-hydroxysteroid dehydrogenase type 2 gene in a case of apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab. 82, 4054–4058 29 Li, A. et al. (1997) Apparent mineralocorticoid excess in a Brazilian kindred: hypertension in the heterozygote state. J. Hypertens. 15, 1397–1402 30 Wilson, R.C. et al. (1995) A mutation in the HSD11Β2 gene in a family with apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab. 80, 2263–2266 31 Mune, T. et al. (1995) Human hypertension caused by mutations in the kidney isozyme of 11β-hydroxysteroid dehydrogenase. Nat. Genet. 10, 394–399 32 Wilson, R.C. et al. (1995) Several homozygous mutations in the gene for 11β-hydroxysteroid dehydrogenase type 2 in patients with apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab. 80, 3145–3150 33 Dave-Sharma, S. et al. (1998) Extensive personal experience: examination of genotype and phenotype relationships in 14 patients with apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab. 83, 2244–2254 34 Wilson, R.C. et al. (1998) A genetic defect resulting in mild low-renin hypertension. Proc. Natl. Acad. Sci. U. S. A. 95, 10200–10205 35 Li, A. et al. (1998) Molecular basis for hypertension in the ‘type II variant’ of apparent mineralocorticoid excess. Am. J. Hum. Genet. 63, 370–379 http://tem.trends.com

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36 Hellman, L. et al. (1971) Renal capture and oxidation of cortisol in man. J. Clin. Endocrinol. Metab. 33, 52–62 37 Monder, C. et al. (1986) The syndrome of apparent mineralocorticoid excess: its association with 11 β-dehydrogenase and 5 β-reductase deficiency and some consequences for corticosteroid metabolism. J. Clin. Endocrinol. Metab. 63, 550–557 38 Morineau, G. et al. (1999) Genetic, biochemical, and clinical studies of patients with A328V or R213C mutations in 11βHSD2 causing apparent mineralocorticoid excess. Hypertension 34, 435–441 39 Shackleton, C.H. et al. (1985) Congenital 11 β-hydroxysteroid dehydrogenase deficiency associated with juvenile hypertension: corticosteroid metabolite profiles of four patients and their families. Clin. Endocrinol. 22, 701–712 40 Stewart, P.M. et al. (1988) Syndrome of apparent mineralocorticoid excess. A defect in the cortisol–cortisone shuttle. J. Clin. Invest. 82, 340–349 41 Batista, M.C. et al. (1986) Spironolactonereversible rickets associated with 11 β-hydroxysteroid dehydrogenase deficiency syndrome. J. Pediatr. 109, 989–993 42 Kitanaka, S. et al. (1996) Apparent mineralocorticoid excess due to 11β-hydroxysteroid dehydrogenase deficiency: a possible cause of intrauterine growth retardation. Clin. Endocrinol. 44, 353–359 43 Sann, L. et al. (1976) Unusual low plasma renin hypertension in a child. J. Clin. Endocrinol. Metab. 43, 265–271 44 Shackleton, C.H. et al. (1980) Hypertension in a four-year-old child: gas chromatographic and mass spectrometric evidence for deficient hepatic metabolism of steroids. J. Clin. Endocrinol. Metab. 50, 786–802 45 Honour, J.W. et al. (1983) Fatal, low renin hypertension associated with a disturbance of cortisol metabolism. Arch. Dis. Child. 58, 1018–1020 46 Milford, D.V. et al. (1995) Mineralocorticoid hypertension and congenital deficiency of 11β-hydroxysteroid dehydrogenase in a family with the syndrome of ‘apparent’ mineralocorticoid excess. Clin. Endocrinol. 43, 241–246 47 Muller-Berghaus, J. et al. (1996) Diagnosis and treatment of a child with the syndrome of apparent mineralocorticoid excess type 1. Acta Paediatr. 85, 111–113 48 Fiselier, T.J. et al. (1982) Low-renin, lowaldosterone hypertension and abnormal cortisol metabolism in a 19-month-old child. Horm. Res. 16, 107–114 49 Harinck, H.I. et al. (1984) Apparent mineralocorticoid excess and deficient 11 β-oxidation of cortisol in a young female. Clin. Endocrinol. 21, 505–514 50 Winter, J.S.D. and McKenzie, J.K. (1977) A syndrome of low-renin hypertension in children. In Juvenile Hypertension (New, M.I. and Levine, S., eds), pp. 123–132, Raven Press 51 Gourmelen, M. et al. (1996) 11 β-Hydroxysteroid dehydrogenase deficit: a rare cause of arterial hypertension. Diagnosis and therapeutic approach in two young brothers. Eur. J. Endocrinol. 135, 238–244 52 Gomez-Sanchez, E.P. et. al. (1995) The modulation of central control of blood pressure. Steroids 60, 69–72

53 Roberts, A.J. and Keith, L.D. (1995) Corticosteroids enhance convulsion susceptibility via central mineralocorticoid receptors. Psychoneuroendocrinology 20, 891–902 54 Gomez-Sanchez, E.P. et al. (1996) Mineralocorticoids, salt and high blood pressure. Steroids 61, 184–188 55 Stewart, P.M. et al. (1995) Type 2 11 β-hydroxysteroid dehydrogenase messenger ribonucleic acid and activity in human placenta and fetal membranes: its relationship to birth weight and putative role in fetal adrenal steroidogenesis. J. Clin. Endocrinol. Metab. 80, 885–890 56 Benediktsson, R. et al. (1995) 11β-Hydroxysteroid dehydrogenase activity in intact dually-perfused fresh human placenta predicts birth weight. J. Endocrinol. 144 (Suppl.), 166 57 Edwards, C.R. et al. (1996) 11 β-Hydroxysteroid dehydrogenases: key enzymes in determining tissue-specific glucocorticoid effects. Steroids 61, 263–269 58 Krozowski, Z. (1999) The 11beta-hydroxysteroid dehydrogenases: functions and physiological effects. Mol. Cell. Endocrinol. 151, 121–127 59 Forest, M.G. et al. (1989) Prenatal treatment in congenital adrenal hyperplasia due to 21hydroxylase deficiency: update 88 of the French multicentric study. Endocr. Res. 15, 277–301 60 Forest, M.G. et al. (1993) Prenatal diagnosis and treatment of 21-hydroxylase deficiency. J. Steroid Biochem. Mol. Biol. 45, 75–82 61 Mercado, A.B. et al. (1995) Extensive personal experience: prenatal treatment and diagnosis of congenital adrenal hyperplasia owing to steroid 21-hydroxylase deficiency. J. Clin. Endocrinol. Metab. 80, 2014–2020 62 Carlson, A.D. et al. (1999) Congenital adrenal hyperplasia: update on prenatal diagnosis and treatment. J. Steroid Biochem. Mol. Biol. 69, 19–29 63 Obeyesekere, V.R. et al. (1995) The R337C mutation generates a high Km 11 βhydroxysteroid dehydrogenase type II enzyme in a family with apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab. 80, 3381–3383 64 Ferrari, P. et al. (1996) Point mutations abolish 11β-hydroxysteroid dehydrogenase type II activity in three families with the congenital syndrome of apparent mineralocorticoid excess. Mol. Cell. Endocrinol. 119, 21–24 65 Ugrasbul, F. et al. (1999) Prevalence of mild apparent mineralocorticoid excess in Mennonites. J. Clin. Endocrinol. Metab. 84, 4735–4738 66 Ulick, S. et al. (1990) Pathogenesis of the type 2 variant of the syndrome of apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab. 70, 200–206 67 Ulick, S. et al. (1992) Defective ring A reduction of cortisol as the major metabolic error in the syndrome of apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab. 74, 593–599 68 Tedde, R. et al. (1992) Evidence for cortisol as the mineralocorticoid in the syndrome of apparent mineralocorticoid excess. J. Endocrinol. Invest. 15, 471–474 69 Mantero, F. et al. (1994) Apparent mineralocorticoid excess type II. Steroids 59, 80–83 70 Palermo, M. et al. (1998) Cure of apparent mineralocorticoid excess by kidney transplantation. New Engl. J. Med. 339, 1787–1788

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71 Soro, A. et al. (1995) Evidence of coexisting changes in 11 β-hydroxysteroid dehydrogenase and 5 β-reductase activity in subjects with untreated essential hypertension. Hypertension 25, 67–70 72 Takeda, Y. et al. (1996) Endogenous renal 11 β-hydroxysteroid dehydrogenase inhibitory factors in patients with low-renin essential hypertension. Hypertension 27, 197–201 73 Walker, B. et al. (1998) Increased glucocorticoid activity in men with cardiovascular risk factors. Hypertension 31, 891–895 74 Walker, B. et al. (1996) Increased vasoconstrictor

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sensitivity to glucocorticoids in essential hypertension. Hypertension 27, 190–196 Weinberger, M. et al. (1986) Definitions and characteristics of sodium sensitivity and blood pressure resistance. Hypertension 8, II127–II134 Weinberger, M. (1996) Salt sensitivity of blood pressure in humans. Hypertension 27, 481–490 Lovati, E. et al. (1999) Molecular basis of human salt sensitivity: the role of the 11β-hydroxysteroid dehydrogenase type 2. J. Clin. Endocrinol. Metab. 84, 3745–3749 Watson, B., Jr et al. (1996) Genetic association of 11 β-hydroxysteroid dehydrogenase type 2

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(HSD11B2) flanking microsatellites with essential hypertension in blacks. Hypertension 28, 478–482 79 Wedel, D.C. (1974) The Story of Alexanderwohl, Mennonite Press 80 Rogoff, D. et al. (1998) The codon 213 of the 11beta-hydroxysteroid dehydrogenase type 2 gene is a hot spot for mutations in apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab. 83, 4391–4393 81 Ulick, S. et al. (1992) Defective ring A reduction of cortisol as the major metabolic error in the syndrome of apparent mineralocorticoid excess. J. Clin. Endocrinol. Metab. 74, 593–599

Glycodelins Markku Seppälä, Hannu Koistinen and Riitta Koistinen Glycodelin is a major glycoprotein that is synthesized in the endometrium in response to progesterone and relaxin exposure. Endometrium-derived glycodelin-A has contraceptive and immunosuppressive properties. Glycodelin is absent from the endometrium during the fertile periovulatory phase, but is synthesized in this tissue during the peri-implantation phase and is abundant during the last week of the luteal phase. Changes in local and/or circulating glycodelin concentrations have been observed in women with reproductive disorders. The chemical modification of glycodelins has resulted in compounds with antiviral activity.

Markku Seppälä* Hannu Koistinen Riitta Koistinen Dept of Obstetrics and Gynecology, Helsinki University Central Hospital, Haartmaninkatu 2, FIN-00290 Helsinki, Finland. *e-mail: [email protected]

In the 1970s and 1980s, several investigators identified a protein in the human placenta, amniotic fluid, pregnancy decidua and seminal plasma and, independently of each other, gave various names to this protein according to the site of detection and/or physicochemical characteristics. Thus, proteins such as chorionic α2-globulin (CAG), placental α2-microglobulin, α-uterine protein (AUP), placental protein 14 (PP14), progestagen-dependent endometrial protein (PEP), pregnancy-associated α2-globulin (α2-PEG) and progesterone-associated endometrial protein (PAEP) were found to be at the very least closely related, if not identical1. In addition to secretory and decidualized endometrium, the protein is synthesized in the fallopian tube, bone marrow, breast, seminal vesicles and various glands in the body1. Remarkable differences were found in the glycosylation of this glycoprotein in various tissues; hence, the names PP14, CAG and placental α2-microglobulin were replaced by glycodelin1–3. Because of differences in their glycosylation, the amniotic fluid glycodelin isoform is called glycodelin-A (GdA) and the corresponding isoform in seminal plasma GdS. Expression Uterus and fallopian tubes

Glycodelin has been localized by immunohistochemical staining to secretory endometrial

glands and to the glandular epithelium of the decidua spongiosa. Maximal staining occurs in the late luteal phase4–6. Human endometrium does not contain detectable glycodelin during days 5–17 of the menstrual cycle4,5, but, in a regular ovulatory cycle, the protein appears 4–5 days after ovulation5,7. Furthermore, the levels increase during the luteal phase but vary in different parts of the endometrium, showing no consistent pattern8. Apart from some retention of glycodelin expression in the basal glands, proliferative endometrium contains little if any glycodelin5,7. During pregnancy, the highest glycodelin concentration in decidual tissue and amniotic fluid is seen at 10–18 weeks (Fig. 1)9. Glycodelin is secreted into uterine fluid in the secretory phase of the cycle10–12. In uterine flushings the glycodelin concentration rises rapidly six days after the ovulatory LH peak (LH+6), with a doubling time of only 6.6 to 14.6 h in the midluteal phase. In the late luteal phase, the glycodelin concentration in uterine flushings is more than 100-fold higher than in the corresponding serum. The concentrations in uterine fluid rise as glycodelin appears in endometrial glands5. The serum glycodelin concentrations were not related to histological dating or morphometric analyses, or to normal or retarded endometrial development. By contrast, the detectable concentrations of glycodelin in uterine flushings did correspond to histological maturation of the endometrium12. Given that the fallopian tubes and the uterus originate from the Mullerian tract it is not surprising that glycodelin is also synthesized in fallopian tubes, with remarkable inter-individual variations13–15. Cyclical variation has been reported for the fimbrial part, where the concentration is higher in the secretory phase of the cycle.

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