Endocrinology and physiology of pseudocyesis

Tarín, Juan J; Hermenegildo, Carlos; García-Pérez, Miguel A; Cano, Antonio

doi:10.1186/1477-7827-11-39

Reproductive Biology and Endocrinology

Table 2 Epidemiological, psychiatric/psychologic, gynecological and endocrinological traits of 10 pseudocyetic women analyzed in 5 studies that fulfilled the inclusion criteria laid down in the Methods section

From: Endocrinology and physiology of pseudocyesis

N° of women	Women’s age (y)	Psychiatric/psychologic traits	Gynecological traits	LH^a	FSH	LH/FSH^a ratio	T^b	E₂	P	GH	PRL^c	Cortisol or DHEAS	Response to inhibitors of the pituitary-adrenal axis	Response to GnRH	TSH and/or response to TRH^e	Response to dopamine agonists (bromocriptine, apomorphine and L-DOPA)^f or opiate antagonists (naloxone)^g	Reference
1	16	Mild depression	Amenorrhea (9 months) and galactorrhea	Elevated with increased frequency of pulses (mid-cycle surge levels)	Within normal range	≈ 5.7	--	Within the mid-follicular phase range	slightly higher than the follicular phase range	Normal diurnal episodic secretion	Distinctly elevated (similar to the mid-cycle surge)	--	--	--	Basal TSH within normal range	--	[34]
1	39	Depression	Amenorrhea (5 months) and galactorrhea	≈ 0.2 IU/L	≈ 14 IU/L	≈ 0.1	--	Within the follicular phase range	Within the follicular phase range	--	Within the normal range	--	--	Normal increase in LH and FSH after GnRH	Normal increase in TSH and PRL, and paradoxical increase in GH (normal basal levels of TSH)	Normal decrease in PRL after bromocriptine and normal decrease in PRL and blunted increase in GH after apomorphine	[35]
1	27	Likely unipolar depressive disorder	Amenorrhea (9 months) and galactorrhea	Within follicular phase range	Within follicular phase range	2.0	Within mid-follicular phase range	Within the mid-follicular phase range	Within mid-follicular phase range	--	Within the normal range	Minimally elevated DHEAS levels	Normal suppression of A.M. cortisol but ACTH remained elevated after overnight low-dose (1 mg) dexamethasone^d	--	Small increase in TSH, normal increase in PRL and paradoxical increase in GH (normal basal levels of TSH and T₄)	--	[32]
5	19, 29, 33, 34, 35	4 women with depression and hysteria	Amenorrhea (4–15 months) and galactorrhea	Within normal range	Within normal range	8.0, 6.6, 2.7, 2.9, 4.4	--	Within normal range (4 women)	1 woman within the follicular phase range, and 4 women slightly higher than the follicular phase range	--	Slightly elevated (4 women) and within the normal range (1 woman)	--	--	--	--	No increase in LH or PRL after naloxone	[33]
1	30	Histrionic personality suffering from major depressive disorder and borderline personality disorder	Amenorrhea (7 months) and galactorrhea	Elevated with frequency of pulses higher than late-follicular phase	Within normal range	≈ 11.3	Consistently elevated	Elevated (late-follicular phase levels)	Not elevated (late-follicular phase levels)	Decreased nocturnal peaks of GH	Normal levels with greater release during sleep than during daytime	Normal cortisol levels rising during sleep and reaching a maximum at 08.00-09.00 h	--	--	--	Decrease in PRL levels and no increase in GH after L-DOPA	[16]
1	38	Histrionic and hypochondriac personality	Amenorrhea (> 5 months) and galactorrhea	Normal with frequency of pulses similar to late-follicular phase	Within normal range	≈ 2.9	Consistently elevated	Elevated (late-follicular phase levels)	Not elevated (late-follicular phase levels)	Decreased nocturnal peaks of GH	Normal levels with greater release during sleep than during daytime	Normal cortisol levels rising during sleep and reaching a maximum at 08.00-09.00 h	--	--	--	Decrease in PRL and no increase in GH after L-DOPA	[16]

^aDespite discrepancies among studies in levels of LH, all the studies included in Table 2 excluding one [35] evidenced LH/FSH ratios higher than 2.0. Moreover, the two studies [16, 34] that measured and analyzed pulsatile patterns of LH in 3 women reported increased (“higher than or similar to the late follicular phase” [16] or “similar to the mid-cycle surge” [34]) frequency of pulses. It is important to stress that these women exhibited high levels of E₂ similar to those found at the late-follicular phase [16], and high levels of PRL similar to those observed mid-cycle just before ovulation [34]. As the frequency of LH pulses increases during the pre-ovulatory period in women with normal menstrual cycles (for review, see McCartney et al. [36]), these data suggest that the 3 pseudocyetic women with high frequency of pulses were in the pre-ovulatory phase of the menstrual cycle at the time blood samples were collected. However, it is very unlikely that the 3 pseudocyetic women restarted ovarian cyclicity just before going to the doctor after being amenorrheic for a long (5 to 7 months). On the contrary, women may have restarted ovarian cyclicity after being informed of her non-pregnant state. In fact, 2 women menstruated 3 [16] and 2 [34] weeks, respectively, after being told that they were not really pregnant (basal hormone determinations were performed before women were informed of their non-pregnant state). Of note, in the woman that menstruated 2 weeks after disclosure of diagnosis, the distended abdomen disappeared within 30 min and the basal levels of LH, PRL and E₂ decreased shortly after being informed of her false pregnancy. All these circumstances support the notion that the higher frequency of LH pulses evidenced in these women was indeed due to their pseudocyetic condition rather than to spontaneous resumption of ovarian cyclicity before going to the doctor.
^bIn these studies, total serum T concentrations were measured by direct radioimmunoassay, a method that suffers from a number of serious problems. This assay often overestimates T concentrations and has limited accuracy at T < 10.4 nmol/L at concentrations typically found in women [37]. Moreover, total serum T levels vary across the menstrual cycle. In normal cycling women, T levels are relatively high at the mid-follicular phase, peaking on the day of LH peak [38, 39]. As mentioned above, despite the 2 women analyzed by Starkman et al. [16] displayed LH pulse characteristics and E₂ and P levels similar to those found at the late-follicular phase, these traits were likely associated to their pseudocyetic condition. Therefore, the “consistently elevated” T levels reported by Starkman et al. [16] cannot be ascribed to women being at the late-follicular phase (when serum T levels are highest). In fact, the 2 women exhibited T concentrations (5.2 and 4.2 nmol/L, respectively) much higher than those observed in normal cycling women at mid-cycle using direct radioimmunoassay (≈3.3 nmol/L [38]), isotope dilution-liquid chromatography-tandem mass spectrometry (1.7 nmol/L [39]) or automated delayed one step chemiluminescent microparticle immunoassay (2.0 nmol/L [39]).
^cAll the women included in Table 2 had galactorrhea despite 50% of them being normoprolactinemic. The absence of correlation between the presence of galactorrhea and levels of PRL may be explained by the fact that blood sample collections were performed in the morning in the majority of the studies. Such a sampling schedule may have concealed the possible occurrence of transient nocturnal hyperprolactinemia associated with galactorrhea and diurnal normoprolactinemia as reported in infertile normoprolactinemic women [40]. In fact, the only study in Table 2 that determined PRL levels in 2 pseudocyetic women during the night [16] reported rising levels during sleep but normal levels during the day. Although the pattern of pituitary PRL release in women with normal cycles follows this circadian rhythm (for review, see Bouilly et al. [41]), the nocturnal PRL concentrations (≈869.6 to ≈ 2174.0 pmol) reported by Starkman et al. [16] are more consistent with those found at night in women with nocturnal hyperprolactinemia, galactorrhea and diurnal normoprolactinemia (608.7 to 1130.4 pmol) than with those displayed by women with normal cycles (347.8 to 608.7 pmol) [40]. Interestingly, the galactorrhea exhibited by women with nocturnal hyperprolactinemia and diurnal normoprolactinemia improved in ≈ 90% (8/9) of cases after treatment with the dopamine agonist bromocriptine [40]. These facts suggest that normoprolactinemic pseudocyetic women (50% in the present review) may have occult hyperprolactinemia due to a deficit in brain dopamine activity.
^dThe discrepancy between the cortisol and adrenocorticotropin hormone (ACTH) response to dexamethasone may be due to the low sensitivity and specificity of the ACTH assay used in this study [42]. However, the fact that after resolution of pseudocyesis both ACTH and cortisol levels decreased after dexamethasone administration suggests that the discordant response observed by Ayers and Seiler [32] was associated with pseudocyesis.
^eAfter resolution of pseudocyesis, women had no GH response to TRH [32, 35] and the blunted or reduced thyroid-stimulating hormone (TSH) response reverted to normal [32] which occurs in patients with major depression after clinical recovery [43, 44]. The mechanism of the paradoxical response of GH to TRH has not been yet elucidated (cited by Arita et al. [45]). However, some authors have speculated about the occurrence of a disruption of the normal neuroendocrine regulatory mechanisms and/or alteration of the cellular receptors of the somatotroph cells in adenomatous tissue [46].
^fDopamine stimulates hypothalamic GH-releasing hormone (GHRH) release [47] but inhibits the high intrinsic PRL secretory activity of the pituitary lactotrophs as well as PRL gene expression and lactotroph proliferation [48]. However, the elevated levels of T displayed by pseudocyetic women may decrease the response of GH to apomorphine and L-3,4-dihydroxyphenylalanine (L-DOPA) since T directly stimulates somatostatin [a.k.a. GH-inhibiting hormone (GHIH) or somatotropin release-inhibiting factor (SRIF)] release from the periventricular nucleus of the hypothalamus (for review, see Spiliotis [49]). It should be emphasized that the decreased GH secretion after apomorphine evidenced by Tulandi et al. [35] reverted to normal after resolution of pseudocyesis.
^gIt is known that endogenous opioid peptides inhibit simultaneously LH and PRL secretion mediated by steroid-dependent suppression of hypothalamic release of GnRH (for review, see Yen et al. [50]). In fact, women with normal cycles exhibit a positive LH and PRL response to naloxone during the late-follicular and mid-luteal phases (when E₂ and P levels are relatively high) but not in the early-follicular phase of the menstrual (for review, see Yen et al. [50]). Note that although the pseudocyetic women analyzed by Devane et al. [33] had P levels “slightly higher” [mean ± standard error of the mean (SEM): 8.9 ± 2.5 nmol/L] than the normal follicular phase range (<3.2 nmol/L [33]), levels of E₂ (200.8 ± 47.7 pmol/L) were within the early follicular range (73.4 to 212.2 pmol/L [51]). Thus, the presence of relatively low levels of E₂ may explain the absence of response of LH and PRL to naloxone evidenced by Devane et al. [33] such as occurs in women with normal cycles in the early-follicular phase cycle or in hypogonadal women (for review, see Yen et al. [50]) and, therefore, it does not support a role for brain opioid peptides in pseudocyesis.

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