Pulsatile secretory characteristics of allopregnanolone, a neuroactive steroid, during the menstrual cycle and in amenorrheic subjects

Abstract

Objective: To investigate whether allopregnanolone, a neuroactive steroid involved in modulating behavioural and neuroendocrine functions, shows episodic secretion in eumenorrheic women, during the follicular and luteal phases of the menstrual cycle, and in women with stress-induced amenorrhea. Patients: Six eumenorrheic women and 14 women with hypothalamic amenorrhea were enrolled for the present study. Methods: All subjects underwent hormonal evaluation in baseline conditions and a pulsatility study to determine LH, cortisol and allopregnanolone episodic release. Eumenorrheic subjects were investigated twice, in the follicular phase (days 3-7) and in the luteal phase (days 18-22) of the menstrual cycle. LH, FSH, prolactin, estradiol, phosphate, DHEA, allopregnanolone and cortisol levels were evaluated in each case. Results: In healthy women, serum gonadotropin and gonadal steroid levels were significantly lower (P , 0:01 and P , 0:05 respectively) than those in amenorrheic subjects. Allopregnanolone was higher in amenorrheic subjects and during the luteal phase, compared with the follicular phase, of eumenorrheic subjects ðP , 0:01Þ: Pulse analysis revealed a significant episodic discharge of allopregnanolone in all subjects (follicular phase 6:5^0:3 peaks/6 h and luteal phase 5:5^0:4 peaks/6 h, hypothalamic amenorrhea 7:0^0:7 peaks/6 h) with higher pulse amplitude in amenorrheic subjects and during the luteal phase compared with the follicular phase of the eumenorrheic subjects ðP , 0:05Þ: Moreover, the specific concordance index demonstrated that allopregnanolone is coupled with LH only during the luteal phase of the cycle and with cortisol during both phases. Allopregnanolone -cortisol coupling was also observed in amenorrheic subjects. Conclusions: Allopregnanolone is secreted episodically. Both the ovary and adrenal glands release this steroid hormone and it shows temporal coupling with LH only during the luteal phase, with cortisol during both the studied phases of the menstrual cycle in eumenorrheic women and again with cortisol in hypothalamic amenorrheic patients.

Studies of pharmacokinetic and pharmacodynamic properties of isoallopregnanolone in healthy women

“…It is known that allopregnanolone and most likely also isoallopregnanolone increase after stress both in humans and animals (Droogleever et al 2004;Purdy et al 1991). The allopregnanolone concentrations at baseline in our subjetcs are slightly lower than in amenorrheic patients known to have a high adrenal stimulation (Genazzani et al 2002). These factors may explain the somewhat higher baseline concentrations of isoallopregnanolone and allopregnanolone in the follicular phase in the present study.…”

“…The first factor is that the baseline samples are all taken early in the morning, that is at a time when ACTH-stimulated steroid production from the adrenals are high. During the follicular phase the ACTH-stimulated adrenals is the major source of serum allopregnanolone and most likely also of isoallopregnanolone (Torres et al 2001, Genazzani et al 2002. The second factor is that the situation was somewhat stressful.…”

Alcohol Intoxication Increases Allopregnanolone Levels in Female Adolescent Humans

“…The plasma samples were extracted with diethyl ether (Genazzani et al, 1998) and the extracts were purified according to Corpechot et al (1993). Since the ovary is an important source of circulating progesterone and allopregnanolone in humans (Rapkin et al, 1997;Genazzani et al, 2002), the study included women in follicular (AAI, n ¼ 10; controls, n ¼ 7) or luteal (AAI, n ¼ 10; controls, n ¼ 8) phases of their ovarian cycle. Their consumption of alcohol was confirmed by the measurement of blood alcohol concentrations, using a gas-chromatographic head-space method described previously by our group (Frias et al, 2002).…”

Neuroactive Steroids are Altered in Schizophrenia and Bipolar Disorder: Relevance to Pathophysiology and Therapeutics

“…In addition, it is possible that menstrual cycle phase in female premenopausal subjects (and hormone replacement status in postmenopausal subjects) may affect neuroactive steroid levels in human brain, since rodent evidence suggests that central allopregnanolone levels fluctuate across the estrous cycle Corpechot et al, 1997;Frye and Bayon, 1998). Peripheral plasma allopregnanolone levels also demonstrate variability across the menstrual cycle in humans (Genazzani et al, 1998(Genazzani et al, , 2002Paul and Purdy, 1992;Pearson Murphy and Allison, 2000). Menstrual cycle phase data and hormone replacement status are unfortunately not available for this tissue collection.…”