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Serum Allopregnanolone in Women With Postpartum "Blues"

From the Department of Obstetrics and Gynecology, Institute for Clinical and Scientific Research (IRCCS) S. Matteo, University of Pavia, Pavia; Department of Obstetrics and Gynecology, University of Siena, Siena; and Department of Obstetrics and Gynecology, University of Pisa, Pisa, Italy.

Address reprint requests to: Rossella E. Nappi, MD, PhD Department of Obstetrics and Gynecology University of Pavia Policlinico S. Matteo Piazzale Golgi 2 27100 Pavia Italy E-mail: renappi{at}tin.it

	Abstract

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Objective: To relate serum allopregnanolone and progesterone levels postpartum to maternity "blues."

Methods: Forty primiparous, healthy, married women (24–39 years of age; at least 13 years of education) who delivered healthy neonates in the Department of Obstetrics at the University of Pavia entered the present study. Blood samples were drawn at 8:30 AM on postpartum day 3 for measurements of serum allopregnanolone, progesterone, cortisol, prolactin, and estradiol. On the same day, every woman was interviewed using the Hamilton Rating Scale for Depression for psychometric testing and completed a self-administered version of the Stein Questionnaire for symptoms of the "blues."

Results: Eighteen of 40 women (45%) experienced maternity "blues" (12 who delivered vaginally and six who delivered by cesarean). Serum allopregnanolone levels were significantly lower in those women experiencing postpartum "blues" with respect to euthymic women (1.1 ± 0.4 versus 2.3 ± 1.0 nmol/L; P < .001), whereas progesterone levels did not differ significantly (11.6 ± 5.6 versus 19.1 ± 15.6 nmol/L; P > .058). Allopregnanolone and progesterone levels correlated significantly in euthymic women (r = .648; P = .001) but not in those with postpartum "blues" (r = .317; P = .199). There was a significant negative correlation between the Hamilton score and levels of serum allopregnanolone (r = -.62; P = .001) and progesterone (r = -.36; P = .024).

Conclusion: Serum allopregnanolone levels were detectable postpartum and were significantly decreased in women with maternity "blues."

The postpartum period is characterized by a strong vulnerability to a wide spectrum of mood disorders.^1–4 At the mildest end of the spectrum is the maternity "blues," occurring in approximately 40–70% of postpartum women within a few days after birth. Less common but more serious is postnatal depression, which generally occurs in about 10% of women several weeks after delivery. A severe form of postpartum psychosis occurs in about 0.1–0.2%.

There is a lack of consensus about the etiology of postpartum affective disorders, and a complex interplay of hormonal, obstetric, and psychosocial factors probably gives rise to the different depressive states.^5,6 However, the dramatic variation in the levels of ovarian steroids is a unique condition postpartum,⁷ and the rapid withdrawal of progesterone has been considered one of the potential candidates in the induction of mood changes.⁸ In addition, some links between postpartum depression and prolactin (PRL) and cortisol levels have been reported, although no clear link has been found for estradiol (E2).^9,10

Allopregnanolone, 3-hydroxy-5-pregnan-20-one, is a ring A-reduced pregnane derivative of progesterone that is synthesized within the central nervous system by the same steroidogenic enzymes found in the gonads and the adrenal glands.^11–13 Experimental studies have identified an involvement of neurosteroids in modulating neuronal excitability, mood, and adaptation to stress.^14,15 Systemic administration of progesterone and its metabolites, including allopregnanolone, induces anxiolytic, hypnotic, and anticonvulsant effects by enhancing the function of -aminobutyric acid A receptors.¹⁴

We have recently shown that serum allopregnanolone levels increase in parallel with progesterone during gestation and parturition, supporting an involvement in the psychological adaptive phenomena associated with pregnancy.¹⁶ On the other hand, increasing evidence of an interaction between neurosteroids and the stress system,^15,17 coupled with the observation that activity of the hypothalamic-pituitary-adrenal axis is impaired postpartum,¹⁸ further suggests that allopregnanolone may be a biochemical marker of maternity "blues" or postnatal depression.¹⁹

Therefore, the aims of the present study were: 1) to measure serum allopregnanolone levels postpartum and their relation to progesterone, and 2) to relate serum allopregnanolone and progesterone levels to maternity "blues."

	Materials and Methods

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From 146 consecutive women who delivered at the Department of Obstetrics at the University of Pavia from September 1999 to November 1999, 40 (30.3 ± 3.6 years; age range 24–39) entered the present study on the third postpartum day. Twenty-eight delivered vaginally and 12 delivered by uncomplicated cesarean for breech presentation or failure to progress. Women were included if they were married, had at least 13 years of education, had a normal pregnancy, were primiparous, gave birth to a healthy neonate, and were breast-feeding at the time of the study. Exclusion criteria were a history of depression or ever taking neuroactive drugs or alcohol abuse. After giving informed consent, each woman fully collaborated with the study protocol. The protocol was approved by the Local Universities Ethical Committee.

In each subject, a catheter was inserted into the antecubital vein at 8:00 AM and a blood sample was drawn at 8:30 AM on postpartum day 3. Blood samples were centrifuged and the serum was stored at -20C until assayed. On the same day, each woman was interviewed individually by the same investigator (REN) for psychometric testing. The Hamilton Rating Scale for Depression was used because it has been established as an accurate tool to detect depression.²⁰ Because this scale includes many questions about physical symptoms and signs that might increase the score during the postpartum period, some questions were omitted from the analysis, as described previously.¹⁸ The "blues" were identified in subjects scoring between 11 and 18. To further confirm the diagnosis of maternity "blues" in our study population, we used a self-administered Italian version of the Stein Questionnaire (cutoff 8)²¹ on postpartum day 3. The diagnosis of maternity "blues" was based on both scores.

Serum levels of allopregnanolone and progesterone were determined as described previously.^16,22 The sensitivity of the allopregnanolone assay, expressed as a minimal amount of allopregnanolone distinguishable from the zero sample with 95% probability, was 15–20 pg/tube, and the intra- and interassay coefficients of variation were 7.2% and 9.1%, respectively. The sensitivity of the progesterone assay was 50 pg/tube, and the intra- and interassay coefficients of variation were 6.5% and 8.7%, respectively.

Plasma levels of cortisol, PRL, and E2 were measured by radioimmunoassay using commercially available kits (Radim SpA, Pomezia, Italy). Sensitivity of the assay was 0.9 µg/dL, 2 ng/mL, and 10 pg/mL, respectively; the intra- and interassay coefficients of variation for cortisol were 4.1% and 6.5%, respectively, for PRL were 4.4% and 6.5%, respectively, and for E2 were 4.6% and 6.9%, respectively.

Data reported in the text were expressed as mean ± standard deviation, and between-subjects analysis was performed with the Student t test. Data reported in the text and in Figure 1 were analyzed by Pearson product-moment correlation, significant at P < .05.

View larger version (28K): [in this window] [in a new window]   Figure 1. Linear correlation between serum allopregnanolone and progesterone levels in euthymic women (A) and in women with postpartum "blues" (B).

	Results

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Serum allopregnanolone levels were significantly lower (P < .001) in those women experiencing postpartum "blues" with respect to euthymic women (1.1 ± 0.4 versus 2.3 ± 1.0 nmol/L), whereas serum progesterone levels were lower (11.6 ± 5.6 versus 19.1 ± 15.6 nmol/L) but without reaching statistical significance (P > .058). Serum allopregnanolone and progesterone levels showed a significant positive correlation (r = .648, P = .001) in euthymic women (Figure 1A), but there was no significant correlation between the hormones (r = .317, P = .199) in women with postpartum "blues" (Figure 1B). There was a significant negative correlation between psychometric scores detected by the Hamilton Rating Scale for Depression and serum levels of allopregnanolone (r = -.62, P = .001) and progesterone (r = -.36; P = .024) in our study population.

Plasma cortisol, PRL, and E2 levels were similar in women with and without maternity "blues" (cortisol: 309.9 ± 37.1 versus 293.0 ± 39.6 nmol/L; PRL: 177.6 ± 22.2 versus 167.9 ± 17 ng/mL; E2: 95.4 ± 12.8 versus 94.2 ± 14.5 pg/mL). No significant differences were found in serum allopregnanolone or progesterone levels, or in plasma cortisol, PRL, or E2 levels, in the postpartum period between women who delivered vaginally and women who delivered by cesarean (data not shown).

	Discussion

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We found serum allopregnanolone levels lower than in pregnancy but still detectable in the postpartum period and significantly decreased in women with maternity "blues," whereas progesterone levels were unchanged in comparison with euthymic women. In addition, whereas allopregnanolone was significantly correlated with progesterone in euthymic women, no significant correlation between these hormones was found in women with maternity "blues." These results seem to confirm the knowledge that neuroactive metabolites, more than progesterone itself, may take part in the complex psychological adjustment to pregnancy and motherhood.^19,23

The origin of "blues" is still unclear and, because it is a common finding, some authors consider it a normal physiologic event that is specific to the puerperium and different from other nonspecific mood fluctuations.²⁴ Women suffering from postpartum "blues" usually have a fourfold increase in the risk of postnatal depression.²⁵ There is common agreement that the abrupt changes in gonadal steroids after birth and the less rapid changes in cortisol and PRL are partially responsible for the symptoms, but different studies have reported contradictory results.^7–9 Harris et al⁹ reviewed the evidence linking hormonal changes with postpartum depressive mood and found modest associations between progesterone levels and postpartum "blues," but no direct association between progesterone and postnatal depression. Development of maternity "blues" was associated with high antenatal salivary progesterone concentrations, low postnatal concentrations, and a greater decrease in the concentration after delivery.⁹ A similar result was not confirmed in plasma.⁵ On the other hand, some authors reported that high progesterone and lower PRL levels predicted the occurrence of depression 6–10 weeks after delivery, particularly in women who were not breast-feeding.⁸

We previously found a progressive increase in serum allopregnanolone during gestation, with the highest levels at term.¹⁶ Thus, we cannot rule out the possibility that the massive decrease detected postpartum in the present study may substantially contribute to the "blues" in sensitive women. Whether neuroactive progesterone metabolites may be responsible for more severe states of postnatal depression remains to be clarified.

The present study supports the concept that progesterone may not be considered a good marker of postpartum mood disorders and shows for the first time that allopregnanolone is a more sensitive indicator of maternity "blues." The lack of correlation between these hormones in this clinical condition leads us to hypothesize that circulating allopregnanolone may reflect a different source or an impaired metabolism of progesterone derived from placental and/or ovarian tissues.

An alternative source for allopregnanolone are the adrenal glands,²² and a dysregulation of the hypothalamic control of adrenal function has been proposed to explain the vulnerability to mood disorders after delivery.¹⁸ Thus, we can hypothesize that a reduced sensitivity and expression of pituitary corticotropin-releasing hormone receptors during the postpartum period, as a consequence of hyperactivity of the hypothalamic pituitary-adrenal axis driven by placental corticotropin-releasing hormone during pregnancy, may persist postpartum and may blunt the adrenal synthesis of allopregnanolone, which in turn may affect maternal mood and behavior. Indeed, we have recently described a similar endocrine situation in hypothalamic amenorrhea,²⁶ which is often associated with mood disorders.²⁷ In addition, the evidence that concentrations of allopregnanolone and progesterone are significantly diminished in women with premenstrual syndrome²⁸ further supports the concept that an impaired anxiolytic -aminobutyric acid A–mediated adaptive response may lead to psychoneuroendocrine symptoms.

We did not find any significant differences in plasma PRL and E2 levels in the early postpartum period in women with and without mood changes, further supporting the inconclusive results of previous reports.¹⁰ Larger studies are needed to fully elucidate the involvement of neurosteroids in the pathogenesis of postpartum mood disorders and to open new perspectives in the development of specific hormonal treatments.

	Footnotes

 
The authors are grateful to Dr. E. Casarosa (Department of Obstetrics and Gynecology, University of Pisa, Italy) and to Dr. A. Poma (Laboratory of Endocrinology, Institute for Clinical and Scientific Research [IRCCS] Mondino, University of Pavia, Italy) for their expert technical assistance and to Dr. R. H. Purdy (Department of Psychiatry, Veterans Administration Hospital, San Diego, CA) for kindly providing allopregnanolone antisera.

PII S0029-7844(00)01112-1

Received May 10, 2000. Received in revised form August 7, 2000. Accepted October 5, 2000.

	References

Top Abstract Materials and Methods Results Discussion References

 
1. Watson JP, Elliott SA, Rugg AJ, Brough DI. Psychiatric disorder in pregnancy and the first postnatal year. Br J Psychiatry 1984;144: 453–62.[Abstract/Free Full Text]

2. Kennerley H, Gath D. Maternity blues reassessed. Psychiatr Dev 1986;1:1–17.

3. Saks BR, Frank JB, Lowe TL, Berman W, Naftolin F, Cohen DJ. Depressed mood during pregnancy and the puerperium: Clinical recognition and implications for clinical practice. Am J Psychiatry 1985;142:728–31.[Abstract/Free Full Text]

4. Stowe JN, Nemeroff CB. Women at risk for postpartum-onset major depression. Am J Obstet Gynecol 1995;173:639–45.[Medline]

5. O’Hara MW, Schlechte JA, Lewis DA, Wright EJ. Prospective study of postpartum blues. Biologic and psychosocial factors. Arch Gen Psychiatry 1991;48:801–6.[Abstract]

6. Kendell RE, Rennie D, Clarke JA, Dean C. The social and obstetric correlates of psychiatric admission in the puerperium. Psychol Med 1981;11:341–50.[Medline]

7. Harris B, Johns S, Fung H, Thomas R, Walker R, Read G, et al. The hormonal environment of postnatal depression. Br J Psychiatry 1989;154:660–7.[Abstract/Free Full Text]

8. Abou-Saleh MT, Ghubash R, Karim L, Krymski M, Bhai I. Hormonal aspects of postpartum depression. Psychoneuroendocrinology 1998;23:465–75.[Medline]

9. Harris B, Lovett L, Newcombe RG, Read GF, Walker R, Riad-Fahmy D. Maternity blues and major endocrine changes: Cardiff puerperal mood and hormone study II. BMJ 1994;308:949–53.[Abstract/Free Full Text]

10. O’Hara MW. Postpartum depression. In: Alloy LB, ed. Series in psychopathology. New York: Springer-Verlag, 1995:1–27.

11. Robel P, Baulieu EE. Neurosteroids: Biosynthesis and function. Trends Endocrinol Metab 1994;5:1–8.

12. Mellon SH, Deschepper CF. Neurosteroids biosynthesis: Genes for adrenal steroidogenic enzymes are expressed in the brain. Brain Res 1993;629:283–92.[Medline]

13. Paul SM, Purdy RH. Neuroactive steroids. FASEB J 1992;6:2311–22.[Abstract]

14. Majewska MD. Neurosteroids: Endogenous bimodal modulators of the GABA_A receptor. Mechanism of action and physiological significance. Prog Neurobiol 1992;38:379–95.[Medline]

15. Mellon SH. Neurosteroids: Biochemistry, modes of action and clinical relevance. J Clin Endocrinol Metab 1994;78:1003–8.[Medline]

16. Luisi S, Petraglia F, Benedetto C, Nappi RE, Bernardi F, Fadalti M, et al. Serum allopregnanolone levels in pregnant women: Changes during pregnancy, at delivery and in hypertensive patients. J Clin Endocrinol Metab 2000;85:2429–33.[Abstract/Free Full Text]

17. Patchev VK, Hassan AHS, Holsboer F, Almeida OFX. The neurosteroid tetrahydroprogesterone attenuates the endocrine response to stress and exerts glucocorticoid-like effects on vasopressin gene transcription in the rat hypothalamus. Neuropsychopharmacology 1996;15:533–40.[Medline]

18. Magiakou MA, Mastorakos G, Rabin D, Dubbert B, Gold PW, Chrousos GP. Hypothalamic corticotropin-releasing hormone suppression during the postpartum period: Implications for the increase in psychiatric manifestations at this time. J Clin Endocrinol Metab 1996;81:1912–7.[Abstract]

19. Majewska MD, Ford-Rice R, Falkay G. Pregnancy-induced alterations of GABAA receptor sensitivity in maternal brain: An antecedent of postpartum "blues"? Brain Res 1989;482:397–401.[Medline]

20. Hamilton M. Development of a rating scale for primary depressive illness. Br J Soc Psychol 1967;6:278–96.

21. Stein GS. The pattern of mental change and body weight in the first postpartum week. J Psychosom Res 1980;24:1165–71.

22. Genazzani AR, Petraglia F, Bernardi F, Casarosa E, Salvestroni C, Tonetti A, et al. Circulating levels of allopregnanolone in humans: Gender, age and endocrine influences. J Clin Endocrinol Metab 1999;83:2099–103.

23. Bitran D, Shiekh M, MacLeod M. Anxiolytic effect of progesterone is mediated by the neurosteroid allopregnanolone at brain GABAa receptors. J Neuroendocrinol 1995;7:171–7.[Medline]

24. Kennerley H, Gath D. Maternity blues II. Associations with obstetric, psychological and psychiatric factors. Br J Psychiatry 1989;155: 367–73.[Abstract/Free Full Text]

25. O’Hara MW, Zekoski EM. Postpartum depression, a comprehensive review. In: Kuman R, Brockington IF, eds. Motherhood and mental illness. London: Wright, 1988:17–57.

26. Meczekalski B, Tonetti A, Monteleone P, Bernardi F, Luisi S, Stomati M, et al. Hypothalamic amenorrhea with normal body weight: ACTH, allopregnanolone and cortisol responses to corticotropin-releasing hormone test. Eur J Endocrinol 2000;142:280–5.[Abstract]

27. Verri AP, Nappi RE, Proietti Cecchini A, Galli C, Luzi S, Zara C. Eating disorders and Axix I psychiatric comorbidity in amenorrheic women. Int J Eat Disord 1998;24:137–46.[Medline]

28. Monteleone P, Luisi S, Tonetti A, Bernardi F, Genazzani AD, Luisi M, et al. Allopregnanolone concentrations and premenstrual syndrome. Eur J Endocrinol 2000;142:269–73.[Abstract]

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