**11. 11β –hydroxysteroid dehydrogenase and pregnancy – role of 11b-HSD type 2 as a protective barrier for fetus to overexposure to glucocorticoids; implication in intrauterine growth retardation**

In mammals, glucocorticoids are important for fetal growth, tissue development and maturation of various organs (surfactant production by the fetal lung, gut enzymes activation and development of the brain and liver). However, supraphysiological levels of glucocorticoids have been shown to cause fetal growth retardation in mammalian models and in human. A number of studies in animal models have examined the effects of prenatal exposure to synthetic glucocorticoids on the fetal development and offspring biology. Maternal glucocorticosteroid treatment reduces birth weight of the offspring and adults exhibit hypertension, hyperinsulinemia, increased hypothalamic–pituitary–adrenal (HPA) axis activity and altered affective behavior [215, 216]). Moreover, human intrauterine growth retardation is associated with high maternal and fetal concentrations of glucocorticoids [217]. Normally, fetal physiological glucocorticoid levels are much lower than maternal levels [218]. The physiological fetoplacental barrier to glucocorticoid exposure is placental 11β-HSD2 that catalyses the rapid conversation of active cortisol and corticosterone to physiologically inert cortisone and corticosterone [219]. 11β-HSD2 acts as a protective barrier to glucocorticoids but a small proportion of maternal glucocorticoid passes through the placenta [220] thus, maternal stress elevates fetal glucocorticoid levels [221]. Different factors are involved in the regulation of placental 11β-HSD2 expression progesterone, estrogen, hypoxia, infection and proinflammatory cytokines reduce placental 11β-HSD2 activity. Conversely, placental 11β-HSD2 activity is stimulated by glucocorticoids, retinoids and leptin [221]. Studies in rats and human indicate that the deficiency in placental 11β-HSD2 activity results in high fetal exposure to maternal glucocorticoids, with subsequent effects on fetal development and birth weight and offspring biology - high plasma cortisol levels, permanent hypertension, hyperglycemia and increased HPA axis activity was present through the adult life [222-224]. Moreover, individuals homozygous for deleterious mutations of *HSD11B2* gene encoding 11β-HSD have low birth weight. Intrauterine growth retardation in human is associated with increased fetal cortisol levels and reduced placental 11β-HSD2 activity [217]. Studies on prenatal exposure to 11β-HSD inhibitors such as glycyrrhetinic acid and carbenoxolone have indicated that these agents cause fetal growth retardation and adult offspring changes that are very similar to those that are caused by prenatal exposure to glucocorticoids such as dexamethasone (readily crosses the placenta) [221]). Mice that are homozygous for disrupted alleles of *HSD11B2* (i.e. 11β-HSD2–/– mice) also have lower birth weight and the offspring display anxiety-related behaviors in adulthood. It seems that the conditions of increased fetal glucocorticoid levels, in response to different maternal restrictions, sometimes have persistent effects in the offspring - so-called concept of developmental physiological programming and that placental 11β-HSD2 is a key player in fetal programming [215, 216, 221].

Hydrohysteroid Dehydrogenases – Biological Role and Clinical Importance – Review 139

cancer, endometriosis

in males associated with obesity, prostate cancer

D-specific bifunctional protein-deficiency, prostate cancer

X-linked mental retardation MHBD

Alzheimer's disease

Breast cancer, prognostic

deficiency

marker

Breast and prostate cancer [230,231]

Breast cancer [233, 234]

Polycystic kidney disease [235, 236]

[240]

[232]

Breast and prostate cancer, endometriosis Abnormal eye develpment

[226, 227]

[10,228]

[229]

[238]

[239]

[241, 242]

[244, 245]

[10,226, 227]

metabolism, and 17β-HSD12 is required in fatty acid elongation. 17β-HSD10 catalyzes the oxidation of short chain fatty acids. 17β-HSD6 and 9 play a role in retinoid conversion. For some 17β-HSDs, the physiological function is not yet clear. For several types of 17β-HSDs participation in the pathophysiology of human diseases has been postulated [225]. The specificity of each 17β-HSD subtype for a preferred substrate together with distinct tissue localization, suggests that these proteins are promising therapeutic targets for diseases like breast cancer, endometriosis, osteoporosis, and prostate cancer. For some of them, their

**Type Gene Function Disease-associations References** 

1 HSD17B1 Steroid (estrogen) synthesis Breast and prostate

3 HSD17B3 Steroid (androgen) synthesis Pseudohermaphroditism

steroid (estrogen, androgen)

prostaglandin) synthesis

epimerase, steroid (androgen)

steroid(estrogen) synthesis

9 HSD17B9 Retinoid metabolism [237]

13 HSD17B13 Not demonstrated [243]

inactivation, estrogens,

acid metabolism, steroid (estrogen, androgen)

steroid(estrogen) synthesis

inactivation, fatty acid

progestin) inactivation

2 HSD17B2 Steroid (estrogen, androgen,

4 HSD17B4 Fatty acid β-oxidation,

5 HSD17B5 Steroid (androgen, estrogen,

6 HSD17B6 Retinoid metabolism, 3α-3β-

7 HSD17B7 Cholesterol biosynthesis,

10 HSD17B10 Isoleucine, fatty acid, bile

11 HSD17B11 Steroid (estrogen, androgen)

14 HSD17B14 Steroid (estrogen, androgen?)

**Table 1.** Human 17β-Hydroxysteroid dehydrogenases

metabolism

12 HSD17B12 Fatty acid elongation,

8 HSD17B8 Fatty acid elongation, steroid

inactivation

inactivation?

androgens

inactivation

inactivation, lipid metabolism?
