Departments of 1 Endocrinología and 2 Obstetricia y Ginecología, Facultad de Medicina, 3 Department of Ciencias Fisiológicas, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
4 To whom correspondence should be addressed at: Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica, Lira 85 5° Piso, Santiago, Chile. Email: pvillase{at}med.puc.cl
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Abstract |
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Key words: bilateral ovariectomy/estrogens/FSH/pregnancy/premature menopause
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Introduction |
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In women, the hormonal profile during physiological pregnancy is well known, characterized by a marked increase in plasma concentrations of estrogens and progesterone (Tulchinsky and Hobel, 1973; O'Leary et al., 1991
; Laird and Parsons, 1996
). Prolactin (PRL) rises continuously from early pregnancy in correspondence with augmenting estrogen levels, and the breast undergoes secretory transformation in preparation for lactation by influence of PRL acting in concert with estrogens and progesterone (Evans et al., 1990
). The withdrawal of progesterone after delivery, together with the sharp rise in circulating PRL induced by suckling, initiate and maintain milk production (Salzman and Cooke, 1996
).
Other studies have measured changes in hormones in late pregnancy and in lactational amenorrhoea in ovary-intact women (Díaz et al., 1991; Tay et al., 1992
; Perheentupa et al., 2000
; Campino et al., 2001
). These reports describe plasma concentrations of FSH and E2 comparable to those in the early follicular phase of the normal menstrual cycle, indicating an inhibition of FSH during lactation.
The role of the ovary in the gonadotrophin suppression during lactation has been studied in different mammalian species: human, non-human primates, sheep, cow, pig, and rat (reviewed in McNeilly, 1994). In these species suckling plays a major role in the suppression of gonadotrophin output from the pituitary during lactation (Gordon et al., 1992
; Ördög et al, 1998
; reviewed in McNeilly, 1994
). Ovariectomy of nursing rhesus monkeys, in contrast to the rapid increase in LH after ovariectomy in cycling females (Atkinson et al., 1970
), resulted in a prolonged delay in the elevation of gonadotrophins (Weiss et al., 1976
); these findings suggested an ovary-independent mechanism whereby suckling suppresses gonadotrophins.
There are no studies evaluating the hormonal profile in ovariectomized pregnant and nursing women. In the case we report, emergency bilateral oophorectomy at week 16 of gestation, due to complications of massive thecalutein cysts, did not interfere with the continuation of pregnancy to term nor with lactation as could be predicted by the knowledge of the endocrine physiology of pregnancy. This unique model stimulated us to study the ovary's role in the hormonal profile at the end of gestation and in lactation and, in particular, to investigate for the first time, the post-partum changes of FSH whilst breastfeeding in the absence of ovaries.
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Case report |
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Lactation commenced spontaneously, and she fully breastfed for 10 days, after which she maintained partial breastfeeding until 10 weeks post-partum, a pattern similar to her previous pregnancies. HRT (transdermal E2 50 µg/day plus oral medroxyprogesterone acetate 5 mg for 12 days per cycle) was commenced at 2 months post-partum because E2 concentration decreased to 136 pmol/l, although the patient experienced no climacteric symptoms. Two weeks later she discontinued lactation.
The patient's body mass index at the beginning of pregnancy was 26.2 kg/m2 and 1 month post-partum was 27.8 kg/m2.
Study protocol
We measured serum FSH, E2, unconjugated estrone (E1), unconjugated estriol (E3), sex hormone-binding globulin (SHBG), dehydroepiandrosterone sulphate (DHEA-S) and PRL at 37 weeks gestation and at 8 h, 4 days, 5 weeks, and 2 months post-partum. Post-suckling PRL was also measured at 4 days, 5 weeks, and 2 months post-partum. Progesterone was measured at 37 weeks gestation and at 4 days and 5 weeks post-partum. Finally, at 3 months post-partum, after weaning and under HRT, we measured FSH, E2, SHBG, and PRL. We did not measure LH at any time.
Laboratory assays
The study of this patient was contemporary with the study by Campino et al. (2001). The same assays were used in both studies to measure E2, E1, E3, SHBG, progesterone, DHEA-S, and PRL. The inter-assay coefficients of variation were: 10.8% for the 1619 pmol/l plasma pool for E2; 9.1% for the 1184 pmol/l E1 plasma pool; 11.2% for the 9.1 nmol/l E3 plasma pool; 7.0% for the 68.5 nmol/l plasma pool for SHBG; 7.8% for the 3.93 nmol/l plasma pool of pregnancy sample progesterone; 8.0% for the 5780 nmol/l plasma pool for DHEA-S; and 9.5% for the 27.7 µg/l plasma pool for PRL. The intra-assay coefficients of variation (CV) were <10% for all the measurements.
FSH concentration was measured by the automated chemiluminescence system (ACS: Centaur; Bayer, USA), using as a standard the Second International Reference Preparation of hMG from the National Institutes of Health (2nd IRP-hMG). This standard was calibrated against LER 907 (human pituitary gonadotrophin extract prepared by Dr Leo E.Reichert Jr); 53 IU of FSH 2nd IRP-hMG correspond to 1 mg of LER 907 (Rosemberg, 1979). Inter-assay CV was 9.6% for the 4.35 IU/l plasma pool and 8.7% for the 13.6 IU/l plasma pool. Intra-assay CV was 3% for concentrations of 6144 IU/l.
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Results |
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After 1 month under HRT and 2 weeks after weaning, plasma E2 concentration increased slightly, and FSH decreased to values similar to those described in estrogen-treated menopausal women (Barnes and Levrant, 1999; Speroff et al., 1999
). Basal PRL concentration (10.2 µg/l) and SHBG (49 nmol/l) reached the levels described in non-nursing women (Campino et al., 1999
).
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Discussion |
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The plasma concentrations of estrogens at the end of gestation in this patient were similar to those in normal pregnant women (Campino et al., 2001). This was expected since, in normal pregnancy, E2 and E1 are synthesized by placental aromatization of maternal and fetal adrenal androgens, mainly DHEA-S (Siiteri and MacDonald, 1966
). Enhanced utilization of DHEA-S in pregnancy lowers maternal plasma DHEA-S levels (Gandy, 1977
; O'Leary et al., 1991
). This was confirmed in this patient by the low concentration of DHEA-S at 37 weeks of gestation that increased to normal non-pregnant levels through puerperium (Gandy, 1977
).
Progesterone concentration at 37 weeks gestation was above the range described in ovary-intact normal pregnant women (Campino et al., 2001). Estrogens increase low density lipoprotein cholesterol uptake by the human placenta (Grimes et al., 1996
) and also increase cytochrome P450 side-chain cleavage enzyme activity in baboon placental microsomes regulating the conversion of cholesterol to pregnenolone, the precursor of progesterone (Babischkin et al., 1997
). We do not know whether the increased plasma progesterone concentration was due to more efficient utilization of substrate or to increased placental enzymatic activity.
Normal estrogen concentrations during pregnancy explain the normal values of SHBG and PRL observed in this patient during pregnancy and postpartum, since estrogens induce the hepatic synthesis of SHBG (Odlind et al., 1982) and stimulate PRL production in the pituitary (Yamamoto et al., 1986
; Blum et al., 1987
; Porter et al., 1990
; Scheithauer et al., 1990
). The low plasma concentration of FSH observed at the end of gestation in the patient may be explained by the suppressive effects of pregnancy hormones upon the hypothalamicpituitary axis (McNeilly, 2001
).
In contrast to the lack of involvement of the ovary in determining the normalcy of reproductive hormones during pregnancy as just discussed, our data suggest that suckling may require the ovary to fully exert its gonadotrophin-suppressing effect. In this oophorectomized nursing patient, basal and post-suckling PRL responses were normal at 5 weeks post-partum, and FSH was normally suppressed in the early puerperium (8 h and 4 days after delivery). The latter could be due to an after-effect of high sex steroids during pregnancy, as shown in nursing and non-nursing ovary-intact women in whom basal FSH concentration is low and its response to GnRH is suppressed until the third week post-partum (Canales et al., 1974; Keye and Jaffe, 1976
). Thereafter, the evolution of post-partum FSH levels in our patient differed from those in ovary-intact breastfeeding women. FSH increased to a peri-menopausal range by 5 weeks after delivery, reaching a close-to-menopausal range at 2 months post-partum, suggesting that the suppressive effect of suckling upon gonadotrophins was reduced in the absence of the ovaries. However, the change of FSH in our patient contrasts with the rapid increase in gonadotrophins (4 days) in non-pregnant women after bilateral oophorectomy (Yen and Tsai, 1971
; Alexandris et al., 1997
), suggesting that suckling restrained the expected gonadotrophin rise in the absence of ovaries. This inhibitory effect of lactation has been described experimentally in ovariectomized nursing rhesus monkeys (Weiss et al., 1976
). In the patient, suckling episodes may have been insufficient to suppress FSH as she did not fully breastfeed; thus, the possibility that the gonadotrophin-suppressing effect of suckling required the presence of the ovary remains open.
In this patient, E2 remained in normal puerperal range and slightly higher than in non-pregnant oophorectomized women (Alexandris et al., 1997). As she was overweight, it is likely that estrogens were derived from peripheral conversion from adrenal androgens in fat tissue (Hansen et al., 1997
; Arlt et al., 1998
; Dragojevic et al., 2004
). At 2 months post-partum, when FSH was close to the menopausal range, the patient was started on 50 µg/day transdermal E2 replacement therapy, a dose which has been demonstrated not to interfere with lactation (Perheentupa et al., 2000
), and FSH decreased as occurs in post-menopausal women treated with HRT. Consistent with her previous nursing history, lactation ended 70 days after delivery.
To summarize, the present data suggest that the gonadotrophin-suppressing effects of suckling during lactation may require involvement of the ovary in women. Pregnant and breastfeeding women who have suffered premature ovarian failure and achieved pregnancy following oocyte donation and IVF may offer further opportunities to explore this possibility.
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Acknowledgements |
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References |
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Submitted on April 6, 2004; resubmitted on July 26, 2004; accepted on October 14, 2004.
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