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Cited by 145Stress Responses and CortisolMenstrual Health and DisordersOvarian function and disorders

Suppression of the Hypothalamic-Pituitary-Ovarian Axis in Normal Women by Glucocorticoids1

Open access
Saketos, Maria, Sharma, Neelam, Santoro, Nanette F.·1993·Biology of Reproduction
DOI 10.1095/biolreprod49.6.1270
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Abstract

To determine whether cortisol has an effect on hypothalamic-pituitary-gonadal function, we studied 11 eumenorrheic women in the early follicular phase of consecutive menstrual cycles by performing daytime 10-min blood sampling, one before and one during hydrocortisone administration. Daily blood sampling for gonadotropins and sex steroids was also performed. LH pulsations were determined by modification of a widely used threshold method and compared by paired t-testing. The LH interpulse interval was significantly prolonged (95 +/- 5 to 119 +/- 14 min; p = 0.001), and the mean LH pulse amplitude remained unchanged (1.3 +/- 0.1 and 1.5 +/- 0.2 mIU/ml) with glucocorticoid exposure. Mean estradiol was not altered (46 +/- 5 and 43 +/- 3 pg/ml), but mean LH and FSH from pooled serum aliquots were slightly but significantly reduced (2.6 +/- 0.2 to 2.2 +/- 0.2, 5.5 +/- 0.4 to 4.5 +/- 0.3 mIU/ml; p = 0.004, 0.012, respectively). Mean progesterone levels were also decreased (0.8 +/- 0.3 to 0.5 +/- 0.2 ng/ml; p = 0.011) in the presence of exogenous glucocorticoid. Twenty-four-hour urinary free cortisol levels confirmed a substantial increase in free cortisol excretion (74 +/- 10 to 305 +/- 50 micrograms/day; p = 0.001). These results demonstrate that cortisol can slow LH pulse frequency and, by inference, hypothalamic GnRH secretion, in a manner that appears independent of corticotropin releasing factor. Excess cortisol alone may therefore play a role in the development of stress-assoc…

Integrity signals

Registry

Crossref · 10.1095/biolreprod49.6.1270

Cites

54 of 54 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 31 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Mean LH pulse amplitude remained unchanged during hydrocortisone administration in the 11 women.

    “the mean LH pulse amplitude remained unchanged (1.3 + 0.1 and 1.5 ± 0.2 mlU/ml) with glucocorticoid exposure.”
    • Also stated in: § 119 · plain
      “Mean LH pulse amplitude remained unchanged (1.3 + 0.1 mIU/ml vs. 1.5 + 0.2 mIU/ml,p = 0.231).”
    Quote in the paperSubstantial claim
  • Findingown data

    Mean serum LH from pooled serum aliquots decreased significantly during hydrocortisone administration.

    “Mean serum LH decreased from 2.6 + 0.2 to 2.2 ± 0.2 mIU/ml (p = 0.004) before and during glucocorticoid administration.”
    Quote in the paperSubstantial claim
  • Findingown data

    Mean serum FSH from pooled serum aliquots decreased significantly during hydrocortisone administration.

    “Mean serum FSH concentrations were also significantly lower: 5.5 ± 0.4 to 4.5 + 0.3 mIU/ml (p = 0.012).”
    Quote in the paperSubstantial claim
  • Findingown data

    Mean serum estradiol was not altered by hydrocortisone administration.

    “Mean serum E concentrations were unchanged (46 + 5 vs. 43 3 pg/ml, p = 0.257)”
    Quote in the paperNot a substantial claim
  • Findingnone given

    All patients experienced subsequent menses at the time expected according to prior cycle length.

    “All patients experienced subsequent menses at the time expected according to prior cycle length.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 12
  • Classified as probably not a substantial claim. 9
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data

    In 11 eumenorrheic women studied in the early follicular phase, hydrocortisone administration significantly prolonged the LH interpulse interval and slowed LH pulse frequency.

    “The LH interpulse interval was significantly prolonged (95 ± 5 to 119 + 14 min;p = 0.001)”
    • Also stated in: § 119 · plain
      “Similarly, LH pulse frequency was significantly slowed (7.7 + 0.4 pulses/12 h vs. 6.6 + 0.5 pulses/12 h,p = 0.007).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Using each woman as her own control in successive early follicular phases is useful for demonstrating differences in LH pulse frequency when interventions are employed, although serial cycle sampling may be relatively insensitive.

    “Therefore, using each woman as her own control in successive early follicular phases is useful for demonstrating differences in LH pulse frequency when interventions are employed, although serial cycle sampling may be relatively insensitive [35].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] 35. Weltman JY, Seip RL, Weltman A, Snead D, Evans WS, Veldhuis JD, Rogol AD. Release of luteinizing hormone and growth hormone after recovery from max- imal exercise. J Appl Physiol 1990; 69:196-200.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Cortisol has been shown to inhibit gonadotropin secretion directly in vitro and indirectly in vivo, as determined by the ability of i.v. GnRH to restore normal gonadotropin secretion in hypogonadotropic, hydrocortisone-treated animals.

    “Cortisol has been shown to inhibit gonadotropin secretion directly in vitro [20] and indirectly in vivo, as determined by the ability of i.v.GnRH to restore normal gonadotropin secretion in hypogonadotropic, hydrocortisone-treated animals [21].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] 20. Padmanabhan V, Keech C, Convey EM. Cortisol inhibits and adrenocorticotropin has no effect on luteinizing hormone-releasing hormone-induced release of lu- teinizing hormone from bovine pituitary cells in vitro. Endocrinology 1983; 112:1782-1787. source
    • cites [21] 21. Dubey AK, Plant TM. A suppression of gonadotropin secretion by cortisol in cas- trated male rhesus monkeys (Macaca mulatta) mediated by the interruption of hypothalamic gonadotropin-releasing hormone release. Biol Reprod 1985; 33:423- 431. source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Hypercortisolemia has been reported in women with menstrual disorders.

    “Hypercortisolemia has also been reported in women with menstrual disorders [2,[5][6][7][8][9][10][11].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2,[5][6][7][8][9][10][11]

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Animal studies have linked increased corticotropin releasing factor (CRF) to decreased LH and FSH secretion and hypercortisolemia.

    “Animal studies have linked increased corticotropin releasing factor (CRF) to decreased LH [12,13] and FSH [12] secretion and hypercortisolemia.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] 12. Olster DH, Ferin M. Corticotropin-releasing hormone inhibits gonadotropin se- cretion in the ovariectomized rhesus monkey. J Clin Endocrinol & Metab 1987; 65:262-267.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [13] 13. Rivier C, Vale W. Influence of corticotropin-releasing factor on reproductive func- tions in the rat. Endocrinology 1984; 114:914-921. source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims. The quote only partly states this claim.

    Study design and conductown data

    Intra- and interassay coefficients of variation for LH and FSH and steroid assays were within specified ranges.

    “Intraassay coefficients of variation (CVs) for LH were 3% at 1 mIU/ml, 2.5% at 5 mIU/ ml, and 2% at 50 mIU/ml; interplate interassay CVs were 6%, 6%, and 4.5%, respectively.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S1 (asserted).

    Premisecitation

    Circulating progesterone in the early follicular phase of the menstrual cycle originates from the adrenal gland.

    “As it has recently been suggested that circulating P in the early follicular phase of the menstrual cycle originates from the adrenal gland [51]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] 51. Judd S, Terry A, Petrucco M, White G. The source of pulsatile secretion of pro- gesterone during the human follicular phase. J Clin Endocrinol & Metab 1992; 74:299-305. source

  • May combine two claims.

    Interpretationreasoning

    The experimental paradigm created a temporary steroid environment similar to that of women with hypothalamic amenorrhea and may serve as a model to study glucocorticoid-mediated pathophysiology.

    “The experimental paradigm used created a steroid environment that was temporary but similar to that of women with hypothalamic amenorrhea and may serve as a model with which to study the pathophysiology of such a glucocorticoid-mediated effect.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Study design and conductcitation

    The LH and FSH assay is sensitive and specific and measures activity against the WHO Second IRP-LH/FSH standard.

    “This assay is sensitive [24] and specific, and measures activity against the WHO Second IRP-LH/FSH standard.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] 24. Santoro N, Schneyer AL, Ibrahim J, Schmidt CL. Gonadotropin and inhibin con- centrations in early pregnancy in women with and without corpora lutea. Obstet Gynecol 1992; 79:579-585.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    The effect of hydrocortisone on ambient progesterone can plausibly be explained if cortisol excess resulted in negative feedback on adrenal progesterone production.

    “the effect of hydrocortisone on ambient P can plausibly be explained if the cortisol excess resulted in negative feedback on adrenal P production.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductreasoning

    It is possible that nonrandomization of patients allowed a consistent bias to be introduced into the study.

    “However, it is also possible that nonrandomization of our patients allowed a consistent bias to be introduced into the study.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductown data

    The low estradiol and progesterone values observed and the agreement with previous investigators confirm that subjects were sampled in the early follicular phase in both study cycles.

    “Although the protocol used here relied solely on menstrual dating of the cycles for planning blood-sampling sessions, the low E and P values observed and the agreement with previous investigators confirm that subjects were sampled in the early follicular phase in both study cycles.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [27] 27. Filicori M, Santoro N, Merriam GR, Crowley WF. Characterization of the physi- ological pattern of episodic gonadotropin secretion throughout the human men- strual cycle. J Clin & Endocrinol Metab 1986; 62:1136-1144. source
    • cites [38] 38. Reame N, Sauder SE, Kelch RP, Marshall JC. Pulsatile gonadotropin secretion dur- ing the human menstrual cycle: evidence for altered frequency of gonadotropin- releasing hormone secretion. J Clin Endocrinol & Metab 1984; 59:328-337.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • May combine two claims.

    Premisecitation

    Direct implantation of CRF into the brain of rodents inhibits LH secretion, and peripheral infusion of CRF decreased LH and FSH secretion in the monkey.

    “Direct implantation of CRF into the brain of rodents was observed to inhibit LH secretion [13], and peripheral infusion of CRF decreased LH and FSH secretion in the monkey [12].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [13] 13. Rivier C, Vale W. Influence of corticotropin-releasing factor on reproductive func- tions in the rat. Endocrinology 1984; 114:914-921. source
    • cites [12] 12. Olster DH, Ferin M. Corticotropin-releasing hormone inhibits gonadotropin se- cretion in the ovariectomized rhesus monkey. J Clin Endocrinol & Metab 1987; 65:262-267.

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    One patient's first 12-h sampling session was stopped after 510 min because of hemoglobin less than 10 g/dl; LH pulse frequency was adjusted for 720 min and reported as 5.6 pulses.

    “In one patient the first 12-h sampling session was stopped after 510 min (8.5 h) because of a hemoglobin level less than 10 g/dl.The LH pulse frequency was adjusted for 720 min and reported as 5.6 pulses.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductreasoning

    The intensive phlebotomy regimen required by this protocol did not allow for daily sampling through a second cycle; therefore subtle changes could not be evaluated.

    “The intensive phlebotomy regimen required by this protocol did not allow for daily sampling through a second cycle; therefore subtle changes could not be evaluated.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Use of hydrocortisone may be one reason why supraphysiologic exposure yielded differences in GnRH secretion.

    “Use of this compound, which binds to corticotropin binding globulin rather than synthetic analogues, may be one reason why supraphysiologic exposure yielded differences in GnRH secretion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Cortisol may act at both the hypothalamic and pituitary levels to reduce GnRH pulse frequency and pituitary LH and FSH secretion.

    “These data suggest that cortisol may act at both the hypothalamic and pituitary levels to reduce GnRH pulse frequency and pituitary LH and FSH secretion.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    Metabolic clearance differences induced by hypercortisolemia may have accounted for the slight but significant decrements in mean LH, FSH, and progesterone.

    “Alternatively, metabolic clearance differences induced by the hypercortisolemia may have accounted for the slight but significant decrements in mean LH, FSH, and P that were observed.”
    Quote in the paperNot a substantial claim
18 of 18

  • The authors state this as an assumption.

    Hydrocortisone administration suppressed endogenous CRF sufficiently that the observed slowing of LH pulse frequency cannot be attributed to CRF.

    “in a manner that appears independent of corticotropin releasing factor.”
    “The experiment described in this report suggests that cortisol can influence LH (and inferentially GnRH) pulse frequency presumably in the face of suppressed CRF.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • In multiple species, psychosocial stress exposure or exogenous CORT inhibited pulsatile LH release.

    “In multiple species, psychosocial stress exposure or treatment with exogenous CORT inhibited the pulsatile release of LH79–81”

    From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [79]

    The Abstract reports that hydrocortisone significantly slowed LH pulse frequency in 11 women, and the Introduction associates stress-related reproductive disorders with reduced pulsatile LH secretion. The paper does not establish that psychosocial stress exposure or exogenous cortisol inhibited pulsatile LH release across multiple species; its cortisol experiment was in women. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Human studies have highlighted the profound effect of glucocorticoid excess on the menstrual cycle.

    “Human studies have also highlighted the profound effect of glucocorticoid excess on the menstrual cycle (Ding et al., 1988; Suh et al., 1988; Saketos et al., 1993; Crofford et al., 1999).”

    From Dynamic Hormone Control of Stress and Fertility (2020) · cites this paper as Saketos et al., 1993

    The Abstract reports that glucocorticoid exposure slowed LH pulses and reduced LH, FSH, and progesterone in women. But the paper’s summary (section “700-”) calls the slowing modest and says it did not disturb the onset of the exposed or subsequent menstrual cycle. This study therefore supports an effect on reproductive hormones, not a profound effect on the menstrual cycle in its participants. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The model provides insight into how a hyper-sensitized HPG axis may explain amenorrhea secondary to high serum cortisol levels.

    “Thus, our model provides insight into how for example a hyper-sensitized HPG axis may explain amenorrhea secondary to high serum cortisol levels (Ding et al., 1988; Suh et al., 1988; Saketos et al., 1993).”

    From Dynamic Hormone Control of Stress and Fertility (2020) · cites this paper as Saketos et al., 1993

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Participants described as both amenorrheic and regularly menstruating

    Minor

    The introduction says the study involved women without menstrual periods, whereas the patient-selection criteria specify regular cycles for all 11 participants.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. [19]19. Luton J-P, Thieblot P, Valcke J-C, Mahoudea JA, Bricaire H. Reversible gonado- tropin deficiency in male Cushing's disease. J Clin Endocrinol & Metab 1977; 45:488-495.
  2. [30]30. Clarke IJ, Cummins JT. The temporal relationship between gonadotropin re leasing hormone (GnRH) and luteinizing hormone (LH) secretion in ovariec tomized ewes. Endocrinology 1982; 111:1737-1739.

Cited by

Sorted by citations

Related

Authors
Saketos, M., Sharma, N., & Santoro, N. F.
Affiliations
Rutgers New Jersey Medical School (US)
Corresponding author
Santoro, Nanette F.
ORCID
Venue
Biology of Reproduction
Publisher
Oxford University Press (OUP)
Published
1993-12-01
Volume
49
Issue
6
Pages
1270-1276
ISSN
  • 0006-3363 (ISSN-L)
  • 1529-7268
DOI
10.1095/biolreprod49.6.1270
OpenAlex
W2096686035
Cited by
145
References
54
Citations by year
2026: 2 · 2025: 6 · 2024: 7 · 2023: 5 · 2022: 2 · 2021: 4 · 2020: 8 · 2019: 2 · 2018: 5 · 2017: 8 · 2016: 4 · 2015: 8 · 2014: 4 · 2013: 6 · 2012: 5
FWCI
0.52
Type
journal article
Language
en
Open access
Locations
  • Biology of Reproduction (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Menstrual Health and Disorders
  • Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
Keywords
glucocorticoids, cortisol, hypothalamic-pituitary-ovarian axis, luteinizing hormone pulsatility, LH pulse frequency, GnRH secretion, gonadotropins, estradiol
MeSH terms
Adult, Estradiol, Female, Follicular Phase, Follicle Stimulating Hormone, Glucocorticoids, Humans, Hydrocortisone

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