Evidence for the Biosynthesis of DHEA from Cholesterol by First-Trimester Human Placental Tissue: Source of Androgens

Abstract

With a view to establishing whether first-trimester human placentas possess the ability to synthesize DHEA from cholesterol, homogenates of this tissue obtained from two groups of women undergoing elective termination of normally progressing pregnancy between 10 - 12 weeks gestation (n = 5, age 23 - 29 years and n = 5, age 21 - 27 years) were incubated separately with [26-(14)C]cholesterol for the generation of [14C]isocaproic acid + pregnenolone and [7n-3H]pregnenolone for the biosynthesis of [3H]DHEA. Controls consisted of homogenates heated in a boiling water bath for 10 min. Using the reverse-isotope dilution analysis, desmolase efficiency expressed as mean specific activity of [14C]isocaproic acid varied from 282 to 725 dpm/mmol, while that of 17 alpha-hydroxylase and steroid C-17,20-lyase, catalyzed conversion of [7n-3H]pregnenolone to [3H]DHEA varied from 3498 to 26 258 dpm/mmol. The corresponding efficiencies of enzymicconversion varied between 5.8 x 10( -2) and 1.5 x 10( -1) % for [14C]isocaproic acid, but between 5.5 x 10( -2) and 4.1 x 10( -1) % for [3H]DHEA. No such metabolite was evident in the controls of heat-denatured homogenates. These are the first study results to demonstrate that early placentas are capable of converting cholesterol to pregnenolone to DHEA, contrary to the widely held concept of DHEA production by fetal and maternal adrenal glands. This finding has important physiological implications and could provide a new dimension to the concept of fetoplacental steroidogenesis.

The Human Placenta Expresses CYP17 and Generates AndrogensDe Novo

“…Historically, most studies have reported a diminished CYP17 activity in the human placenta, except for two reports from the 1960s (11,12) and most recently by Loganath et al (13), who also reported pregnenolone to DHEA conversion in fetal chorion (14) and amnion (15). We were able to demonstrate that isolated midterm human placental cells as well as JEG-3 choriocarcinoma cells are capable of synthesizing estrogens de novo without the addition of androgen precursors to the media.…”

Improvement in diminished ovarian reserve after dehydroepiandrosterone supplementation

“…Adverse side effects have been limited to oily skin, rarely mild acne vulgaris and mild hair loss. Since first-trimester placenta produces DHEA (Loganath et al, 2002), maternal DHEA exposure at moderate dosages in very early pregnancy should not constitute significant risk.…”

Metformin prevents embryonic resorption induced by hyperandrogenisation with dehydroepiandrosterone in mice

“…During pregnancy, DHEA and DHEAS have immunoregulatory actions on the maternal immune system (Nieschlag et al 1974;Facchinetti et al 1986;Tagawa et al 2004). Not only maternal adrenal glands (Nieschlag et al 1973) but also early placenta and fetal adrenal glands are capable of converting cholesterol to pregnenolone to DHEA (Loganath et al 2002). Therefore, serum DHEA suppresses immune reactions by modifying cytokine levels and thus contributing to the development of gestation (Nieschlag et al 1974;Du et al 2001;Tagawa et al 2004).…”