O estrogênio promove a produção de cortisolɁ
Estrogênio: hormônio sexual e hormônio do estresseɁ Como assimɁ
[Imagem: gemotest.ru]
É comum que o estrogênio, tido apenas como hormônio sexual, e o cortisol, notoriamente entendido como hormônio do estresse, não sejam vinculados entre si. Cada um fica na sua caixinha. Sem relação direta alguma.
Muita gente não imagina que tais hormônios, um deles que se sabe vinculado ao estresse emocional, cortisol, e o outro que é apenas pensado como envolvido com processos do aparelho reprodutor feminino, possam se conectar bioquimicamente. Muito menos que um gere a síntese do outro, ainda mais difícil aceitar a ideia de que o estrogênio é capaz de gerar o cortisol.
O problema com essa ideia do estrogênio gerando cortisol, é que ela não apenas é real do ponto de vista fisiológico – como tantas vezes já foi explicado por R. Peat – como aqui e ali, principalmente tempos atrás, são elaboradas pesquisas pontuais mostrando isso.
Existe uma experiência de primeira grandeza, feita em humanos, elaborada muito engenhosamente, nos anos 90, e que mostra sem margem a dúvida que o aumento do estrogênio promove a síntese de hormônios do estresse que incluem o cortisol; não somente este, mas também o ACTH, adrenalina, hormônios do eixo hipófise-adrenal.
A experiência abaixo [A] mostra que o hormônio chamado sexual, o estrogênio, controla e impacta diretamente o eixo hipófise-adrenal, de tal forma que promove aumento do cortisol.
A experiência, feita em humanos, utilizando inclusive uma quantidade mínima de estrogênio, mostrou – de forma incontornável – que o aumento de estrogênio corporal eleva os níveis de cortisol e de outros hormônios do estresse no corpo.
Então sim, o estrogênio tem um efeito pró-estresse, pela via da promoção do aumento do cortisol.
Já foi demonstrado mais uma vez, em outras áreas do corpo humano, como o sistema sanguíneo, pele e outros órgãos como o fígado, que o estrogênio tem um efeito nefasto contra a nossa biologia, pela via do cortisol. Essa pesquisa [A] confirmou isso.
Ela foi organizada da seguinte forma: 16 adultos, conformando grupo controle de um lado e grupo placebo do outro, receberam, no caso de um dos grupos, um implante transdérmico de estrogênio que liberava 01 mg de estradiol diariamente; o outro grupo, chamado placebo, não recebeu estradiol. Apenas 48 horas depois, o grupo controle e o placebo foram expostos a um tipo de estresse, psicossocial e, após este evento, foram submetidos a exames laboratoriais.
O estresse consistiu em colocar os homens na frente de uma grande plateia e eles foram induzidos a fazer discursos. Ficou evidente que houve um bom grau de estresse.
Todos foram examinados antes em relação a algumas variáveis psíquicas e todos foram examinados depois, igualmente, para que se estabelecesse um padrão de homogeneização do perfil das pessoas que, ao final, passariam por aquele estresse psicossocial.
O resultado em todos os dois grupos, foi de aumento dos níveis plasmáticos de cortisol, ACTH e adrenalina. Até aqui, sem novidades. Qualquer tipo de estresse importante aumenta esses hormônios [que são vinculados a processos de estresse].
A novidade foi que os hormônios aumentaram em uma taxa significativamente mais alta naqueles que receberam a minidose de estrogênio [e isso, atenção, apenas por nada mais que dois dias].
A conclusão dos cientistas: a administração por curto prazo de estradiol resultou numa hiper-resposta do eixo hipófise-adrenalina ao estresse psicológico em homens jovens saudáveis, conforme foi documentado no estudo.
Ou seja, mais uma vez estabelecida a relação direta fisiológica entre o estrogênio e o cortisol. Estrogênio promovendo síntese de cortisol.
Não é razoável, então, que muita gente continue falando, nesse caso indevidamente, que o estrogênio não é um hormônio do estresse. E não seja tampouco levado em conta o feedback que permite que cortisol induza produção de estrogênio também, ambos conduzindo o processo do mau envelhecimento.
As evidências fisiológicas são de que, para além dos seus efeitos sexuais, o estrogênio é, por excelência, um promotor da produção de cortisol.
Outra experiência já tinha sido feita, por exemplo, através da injeção de estrogênio no cérebro de animais, dando como resultado a liquidação total de parte do tecido cerebral, aquela parte que foi alcançada pelo estrogênio. Em artigo anterior foi mostrado que ele inibe a respiração celular e aumenta a calcificação das células, degradando o tecido cerebral também .
Experiências já demonstraram que o estradiol aumenta a secreção basal de ACTH [enquanto andrógenos reduzem a eficácia do feedback negativo do cortisol][O]. Um estudo [C] conclui positivamente que a hiperativação do eixo hipotálamo-hipófise-adrenal pode ser promovida pelo estrogênio.
Os esteroides sexuais, conclui outro estudo, modulam a atividade do eixo hipófise-adrenal [F]. E outro [H] demonstrou estimulação da produção de cortisol pelo estrogênio.
Tudo isso levanta o debate sobre a irresponsabilidade terapêutica do uso de estrogênio nas chamadas “reposições” hormonais. E também do cortisol, com a facilidade e o uso continuado como acontece em prescrições médicas.
Por queɁ Porque independentemente da intenção do doutor, os efeitos nefastos tendem a acontecer, a partir do uso do estrogênio [também do cortisol].
Fica invariavelmente claro que não existe uma muralha entre hormônios sexuais de um lado e hormônios do estresse do outro.
Eles se sobrepõem em suas ações e pelos feedbacks entre si, sendo que, no caso, a conexão já foi mais de uma vez estabelecida entre aumento de estrogênio e aumento dos níveis de cortisol – portanto de mais estresse – no organismo.
GM Fontes, Brasília, 8-4-24
As informações aqui presentes não pretendem servir para uso diagnóstico, prescrição médica, tratamento, prevenção ou mitigação de qualquer doença humana. Não pretendem substituir a consulta ao profissional médico ou servir como recomendação para qualquer plano de tratamento. Trata-se de informações com fins estritamente educativos. Nenhuma das notas aqui presentes, neste blog, conseguirá atingir o contexto específico do paciente singular, nem doses, modo de usar etc. Este trabalho compete ao paciente com seu médico. Isso significa que nenhuma dessas notas - necessariamente parciais - substitui essa relação.
Referências _______________
[A bibliografia a seguir procede, integralmente, do artigo de R. Peat intitulado Estrogen and brain aging in men and women: depression, energy, stress ]
[A] KIRSCHBAUM C SCHOMMER N FEDERENKO I, 1996. Short-term estradiol treatment enhances pituitary-adrenal axis and sympathetic responses to psychosocial stress in healthy young men. J Clin Endocrinol Metab. 1996 Oct;81(10):3639-43. doi: 10.1210/jcem.81.10.8855815. PMID: 8855815 DOI: 10.1210/jcem.81.10.8855815 “Evidence from animal studies and clinical observations suggest that the activity of the pituitary-adrenal axis is under significant influence of sex steroids. The present study investigated how a short term elevation of estradiol levels affects ACTH, cortisol, norepinephrine, and heart rate responses to mental stress in healthy men. In a double blind study, 16 men received a patch delivering 0.1 mg estradiol/day transdermally, and age- and body mass index-matched control subjects received a placebo patch. Twenty-four to 48 h later, they were exposed to a brief psychosocial stressor (free speech and mental arithmetic in front of an audience). In response to the psychosocial stressor, ACTH, cortisol, norepinephrine, and heart rate were increased in both experimental groups (all P < 0.0001). However, the estradiol-treated subjects showed exaggerated peak ACTH (P < 0.001) and cortisol (P < 0.002) responses compared to the placebo group. Also, the norepinephrine area under the response curve was greater in the estradiol group (P < 0.05). Although heart rate responses differences failed to reach statistical significance, they, too, tended to be larger in the estradiol group. Neither mood ratings before or after the stressor, nor ratings of the perception of the stressor could explain the observed endocrine response differences. In conclusion, short term estradiol administration resulted in hyperresponses of the pituitary-adrenal axis and norepinephrine to psychosocial stress in healthy young men independent of psychological effects, as assessed in this study”.
[B] WHITE-WELKLEY J E WARREN G L, 1996. Treadmill exercise training and estradiol increase plasma ACTH and prolactin after novel footshock. J Appl Physiol (1985). 1996 Mar;80(3):931-9. doi: 10.1152/jappl.1996.80.3.931. PMID: 8964759 DOI: 10.1152/jappl.1996.80.3.931 “We examined whether rats that were treadmill exercise trained (Tr) or chronically immobilized (CI) had similar responses by the hypothalamic-pituitary-adrenal (HPA) cortical axis to acute stress and whether the HPA responses interacted with the hypothalamic-pituitary-gonadal (HPG) axis. After 6 wk (1 h/day, 6 days/wk) of Tr or CI, plasma concentrations of adrenocorticotropic hormone ([ACTH]), [prolactin], and [corticosterone] were measured after familiar (treadmill running or immobilization) or novel (footshock) stress. Ovariectomized Sprague-Dawley females (n = 72) were implanted with capsules containing estradiol benzoate (E2) and randomly assigned in a 2-group (E2 vs. no E2) x 3 treatment (Tr vs. CI vs. sedentary) x 4 acute stressor [footshock vs. treadmill running (Run) vs. immobilization (Im) vs. no stress] x 3 recovery time (1 vs. 15 vs. 30 min) mixed-model analysis of variance. E2 capsules were removed from one-half of the animals 48 h before the first stressor session. After 10 min of acute stress, blood was drawn from a jugular catheter at 1, 15, and 30 min of recovery. [ACTH] and [prolactin] after footshock were higher in Tr rats with E2 compared with CI and sedentary rats without E2; recovery levels for sedentary animals were higher after Run compared with Im. The elevation in [corticosterone] from minute 1 to 15 of recovery was higher after the familiar Run and Im conditions. Our findings are consistent with an increased responsiveness of the HPA axis to novel footshock after treadmill exercise training that is additionally modulated by the HPG axis.
[C] BURGESS L H HANDA R J, 1992. Chronic estrogen-induced alterations in adrenocorticotropin and corticosterone secretion, and glucocorticoid receptor-mediated functions in female rats. Endocrinology. 1992 Sep;131(3):1261-9. doi: 10.1210/endo.131.3.1324155. PMID: 1324155 DOI: 10.1210/endo.131.3.1324155 “The effect of estrogen (E) on the hypothalamic-pituitary-adrenal axis was investigated in female Sprague-Dawley rats. Animals were bilaterally ovariectomized (OVX), and a Silastic capsule (0.5 cm) containing 17 beta-estradiol was sc implanted. Control animals received a blank capsule. Animals were killed 21 days later. In E-treated rats, we found significantly higher corticosterone (CORT) peak levels 20 min after a 5-sec footshock (1.0 mamp) or exposure to ether vapors (P less than 0.05) compared to those in OVX controls. In addition, the recovery of the ACTH and CORT responses to footshock stress was significantly prolonged (P less than 0.05) in the presence of E. Furthermore, the ACTH and CORT secretory responses to ether stress could be suppressed by exogenous RU 28362 (a specific glucocorticoid receptor agonist; 40 micrograms/100 g BW for 4 days) in OVX controls (P less than 0.05), but not in E-treated animals. These data suggest that E can impair glucocorticoid receptor-mediated delayed or slow negative feedback. Consequently, we examined the influence of E on mineralocorticoid and glucocorticoid receptor concentrations using in vitro binding assays. E did not alter mineralocorticoid or glucocorticoid receptor concentrations in any of the brain regions examined. The administration of RU 28362 (40 micrograms/100 g BW for 4 days) to OVX control or E-treated rats significantly down-regulated hippocampal glucocorticoid receptor (P less than 0.02) in control rats only. In contrast, aldosterone administration (40 micrograms/100 g BW for 4 days) significantly down-regulated hippocampal glucocorticoid receptor (P less than 0.0008) in both control and E-treated animals. Thus, E treatment results in a loss of the glucocorticoid receptor's ability to autoregulate; this suggests that E may cause a functional impairment of the glucocorticoid receptor even though receptor binding appears normal. These findings suggest that hyperactivation of the hypothalamic-pituitary-adrenal axis after stress in E-treated rats is due in part to impaired glucocorticoid receptor-mediated slow negative feedback.
[D] CARMINA E LOBO R A, 1994. Ovarian suppression reduces clinical and endocrine expression of late-onset congenital adrenal hyperplasia due to 21-hydroxylase deficiency. Fertil Steril. 1994 Oct;62(4):738-43. doi: 10.1016/s0015-0282(16)56998-2. PMID: 7926082 DOI: 10.1016/s0015-0282(16)56998-2 “Objective: To determine the effectiveness of GnRH-agonist (GnRH-a) treatment in women with late onset congenital adrenal hyperplasia. Design: Prospective assessment of GnRH-a treatment in six women with documented late-on-set congenital adrenal hyperplasia who were not preselected. Comparisons were made to previous responses in the same patients receiving dexamethasone. Eight age- and weight-matched ovulatory women served as controls. Setting: Academic medical center. Intervention: Baseline blood determinations before and after i.v. ACTH, before and after 6 months of GnRH-a treatment. Estrogen and progestin replacement was begun in all women after the 3rd month of treatment. Main outcome measures: Serum 17-hydroxyprogesterone (17-OHP), gonadotropin, and androgen levels before and after GnRH-a treatment. Responses of 17-OHP and androgens to ACTH assessment of hirsutism using a modified Ferriman-Gallwey score. Results: Gonadotropins, estrogen, androgen, and 17-OHP were suppressed with GnRH-a treatment. Levels were similar before and after estrogen and progestin replacement. Responses of 17-OHP after ACTH were blunted but still were elevated compared with responses in controls. Ferriman-Gallwey scores decreased significantly (-8 +/- 1; mean +/- SE). This response was greater than that observed previously with 6 months of dexamethasone (-2 +/- 0.3). Conclusions: Suppression of the ovary with GnRH-a treatment was beneficial in these patients with late-onset congenital adrenal hyperplasia. An ovarian influence on the clinical and biochemical findings of the disorder is suggested”.
[E] NOWAK K W NERI G, 1995. Effects of sex hormones on the steroidogenic activity of dispersed adrenocortical cells of the rat adrenal córtex. Life Sci. 1995;57(9):833-7. doi: 10.1016/0024-3205(95)02015-b PMID: 7630311 DOI: 10.1016/0024-3205(95)02015-b “The effect of 17 beta-estradiol and testosterone on glucocorticoid secretion were studied in vitro by using dispersed inner adrenocortical cells obtained from gonadectomized female and male rats. Independently of the sex of animals, estradiol enhanced basal, but not ACTH-stimulated corticosterone (B) secretion; conversely, testosterone inhibited ACTH-stimulated, but not basal B output. HPLC analysis of steroid secreted demonstrated that estradiol induced comparable rises (53-62%) in basal pregnenolone (PREG) and total post-PREG secretion (progesterone, 11-deoxycorticosterone and B). Testosterone inhibited by about 30% ACTH-stimulated PREG production and by about 54% total post-PREG secretion (B was decreased to 56% of the control value, and other steroid hormones were below the limit of sensitivity of our assay system). These findings indicate that sex hormones directly affect rat adrenocortical secretion, mainly by acting on the rate-limiting step of steroidogenesis (i.e. the conversion of cholesterol to PREG); moreover, they suggest that testosterone is also able depress the activity of the enzymes operating distally to cholesterol side-chain cleavage.
[F] CAREY M P DETERD C H, 1995. The influence of ovarian steroids on hypothalamic-pituitary-adrenal regulation in the female rat. J Endocrinol. 1995 Feb;144(2):311-21. doi: 10.1677/joe.0.1440311. ID: 7706984 DOI: 10.1677/joe.0.1440311 “The present study examined the association between hypothalamic-pituitary-adrenal (HPA) and hypothalamic-pituitary-ovarian axes. HPA activity determined by plasma levels of adrenocorticotropin (ACTH) and corticosterone (B) was assessed in intact female rats as a function of oestrous cycle stage under resting conditions and after exposure to a 20 min restraint stress. To delineate the roles of oestradiol and progesterone in HPA axis modulation, plasma concentrations of ACTH and B were determined in ovariectomised (OVX) animals treated with oestradiol and/or progesterone under resting conditions and during exposure to the stress of a novel environment. The effects of these steroid treatments on the transcription and/or binding properties of the two corticosteroid receptors, the mineralocorticoid (MR) and glucocorticoid (GR) receptors, were also examined in hippocampal tissue, (i) Fluctuations in basal and stress-induced plasma ACTH and B concentrations were found during the oestrous cycle with highest levels at late pro-oestrus. (ii) In OVX steroid-replaced animals, basal and stress-induced activity was enhanced in oestradiol and oestradiol plus progesterone-treated animals compared with OVX controls. (iii) Cytosol binding assays revealed an oestradiol-induced decrease in hippocampal MR capacity. This decrease appears to be due to an effect of the steroid on MR transcription as in situ hybridisation analysis of MR mRNA showed an oestradiol-induced decrease in MR transcript in all hippocampal subfields. (iv) Treatment of oestradiol-primed animals with progesterone reversed the oestradiol-induced decrease in hippocampal MR capacity. Data from MR mRNA hybridisation in situ experiments indicate that this reversal may be due to an antagonism of the oestradiol effect on MR transcription. (v) Progesterone treatment with or without prior oestradiol-priming induced a significant decrease in the apparent binding affinity of hippocampal MR. We show that progesterone and its 11 beta-hydroxylated derivative have a high affinity for the hippocampal MR. (vi) Neither oestradiol nor progesterone affected GR binding parameters in the hippocampus. In conclusion, we find that sex steroids modulate HPA activity and suggest that the observed effects of these steroids on hippocampal MR may underlie their concerted mechanism of action in inducing an enhanced activity at the period of late pro-oestrus.
[G] MESIANO S JAFFE R B, 1993. Interaction of insulin-like growth factor-II and estradiol directs steroidogenesis in the human fetal adrenal toward dehydroepiandrosterone sulfate production. J Clin Endocrinol Metab. 1993 Sep;77(3):754-8. doi: 10.1210/jcem.77.3.8396578. PMID: 8396578 DOI: 10.1210/jcem.77.3.8396578 “We examined the regulation of steroid production in fetal zone cells from midgestation (16-21 weeks) human fetal adrenal glands to elucidate the mechanism by which these cells secrete large quantities of dehydroepiandrosterone sulfate (DHAS) and little cortisol in response to ACTH. Our underlying hypothesis is that estrogen and insulin-like to ACTH. Our underlying hypothesis is that estrogen and insulin-like growth factor-II (IGF-II) modulate the steroidogenic response of fetal zone cells to ACTH, driving steroid production toward DHAS rather than cortisol. We also hypothesize that the effects of IGF-II and estrogen on steroidogenesis are achieved by modulating the expression of key enzymes in the steroidogenic pathway. Basal cortisol secretion by cultured fetal zone cells was below the limit of assay sensitivity (< 0.54 pmol/10(5) cells.24 h), whereas basal DHAS secretion was 210.8 +/- 41.0 pmol/10(5) cells.24 h (mean +/- SE). ACTH-(1-24) increased the secretion of cortisol to 228.96 +/- 6.75 pmol/10(5) cells.24 h and that of DHAS to 2039.8 +/- 121.7 pmol/10(5) cells.24 h. Neither IGF-II nor estradiol (E2) affected basal (no added ACTH) steroid secretion by fetal zone cells. IGF-II increased ACTH-stimulated cortisol and DHAS secretion by fetal zone cells in a dose-dependent fashion. In contrast, E2 at high concentrations (1-10 mumol/L) decreased ACTH-stimulated cortisol production to basal levels, but increased ACTH-stimulated DHAS production 1.5- to 2-fold. Combinations of IGF-II (100 ng/mL) and E2 (1 mumol/L) increased ACTH-stimulated cortisol and DHAS secretion by 1.5- to 2-fold compared with control values. However, compared with cultures exposed to IGF-II alone, inclusion of E2 decreased ACTH-stimulated cortisol secretion by about 60% and increased ACTH-stimulated DHAS secretion by about 50%. IGF-II increased the abundance of ACTH-stimulated mRNAs encoding cholesterol side-chain cleavage cytochrome P450 (P450scc), 17 alpha hydroxylase/17,20 lyase P450 (P450c17), and 3 beta-hydroxysteroid dehydrogenase (3 beta HSD). In addition, IGF-II increased the abundance of mRNA encoding P450c17 under basal conditions, but did not affect the basal expression of P450scc or 3 beta HSD. E2 had no effect on basal expression of these steroidogenic enzymes, but increased the abundance of ACTH-stimulated mRNA encoding P450scc and P450c17. The abundance of mRNA encoding 3 beta HSD was not affected by E2. The effect of IGF-II and E2 in combination on steroidogenic enzyme mRNA abundance was not different from that of IGF-II alone. These data indicate that IGF-II increases ACTH-stimulated steroid production in fetal zone cells by increasing the expression of key steroidogenic enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)
[H] CATICHA O ODELL W D, 1993. Estradiol stimulates cortisol production by adrenal cells in estrogen-dependent primary adrenocortical nodular dysplasia. J Clin Endocrinol Metab. 1993 Aug;77(2):494-7. doi: 10.1210/jcem.77.2.8345057. PMID: 8345057 DOI: 10.1210/jcem.77.2.8345057 Adrenal glands from a patient with ACTH-independent Cushing's syndrome, whose symptoms worsened during pregnancy and oral contraceptive use, were cultured in different concentrations of estradiol. Estradiol stimulated cortisol secretion in a dose-response manner in the absence of ACTH. Since immunoglobulins G from this patient did not stimulate corticosterone production in a mouse adrenal bioassay, an adrenal-stimulating immunoglobulin is unlikely to be the cause of adrenal hyperfunction in this case. This is the first description of estradiol stimulation of cortisol production by cultured adrenal cells in ACTH-independent Cushing's syndrome.
[I] SPINEDI E SUESCUN M O 1992. Effects of gonadectomy and sex hormone therapy on the endotoxin-stimulated hypothalamo-pituitary-adrenal axis: evidence for a neuroendocrine-immunological sexual dimorphism. Endocrinology. 1992 Nov;131(5):2430-6. doi: 10.1210/endo.131.5.1330501. PMID: 1330501 DOI: 10.1210/endo.131.5.1330501 “Bacterial lipopolysaccharide (LPS) stimulates the hypothalamo-pituitary-adrenal axis by a mechanism involving the release of cytokines, which activate the CRH-ACTH system and, as a result, increase glucocorticoid secretion. In the present study we investigated the possibility that endogenous sex hormones modulate the in vivo endotoxin-stimulated adrenal and immune responses in adult BALB/c mice. In preliminary experiments we determined that the maximal glucocorticoid release in response to LPS (50 micrograms, ip) administration was reached 2 h after treatment. The endotoxin effect on the adrenal and immune responses was then tested in male, randomly cycling female, 20-day-gonadectomized and 20-day-gonadectomized mice treated with either testosterone or estradiol. In addition, in vitro experiments were performed to determine whether 1) LPS exerts any direct effect on basal and ACTH-stimulated corticosterone release, and 2) adrenal function is influenced by bilateral gonadectomy and sex steroid therapy. Our results indicate that 1) randomly cycling female mice have significantly more pronounced corticosterone secretion than males 2 h after endotoxin injection, although the tumor necrosis factor responses were similar; 2) the response of the hypothalamo-pituitary-adrenal axis to endotoxin stimulation in female mice was invariable throughout the different stages of the normal estrous cycle; 3) gonadectomy leads to enhanced (P < 0.05) adrenal and immune responses to LPS stimulation compared to the responses in shams; 4) the endotoxin-elicited adrenal and immune overresponses observed in gonadectomized mice are reversed by testosterone treatment, regardless of sex; 5) LPS does not directly modify spontaneous and ACTH-stimulated adrenal corticosterone secretion; and 6) gonadectomy alone or combined with sex steroid therapy does not increase the in vitro adrenal response to ACTH stimulation. Our findings further suggest an evident neuroendocrine-immunological sexual dimorphism during the acute phase of inflammatory processes.
[J] KERDELHUE B JONES G S 1995. Activation of the hypothalamo-anterior pituitary corticotropin-releasing hormone, adrenocorticotropin hormone and beta-endorphin systems during the estradiol 17 beta-induced plasma LH surge in the ovariectomized monkey. J Neurosci Res. 1995 Oct 1;42(2):228-35. doi: 10.1002/jnr.490420210. PMID: 8568923 DOI: 10.1002/jnr.490420210 “The present work describes time-dependent changes in the content of corticotropin-releasing hormone (CRH), adrenocorticotropin (ACTH), and beta-endorphin (beta-EP) in the hypothalamus (HT) and anterior pituitary (AP) and in the concentration of ACTH and beta-EP in the plasma during the 17 beta estradiol (E2) benzoate (E2B)-induced luteinizing hormone (LH) surge in ovariectomized cynomolgus monkeys. Monkeys were euthanized at 0, 30, 48, 72, and 96 hr post-E2B. HT and AP were rapidly dissected, extracted in 2 N acetic acid containing 1 mM phenylmethane sulfonyl fluoride at 4 degrees C, and centrifuged at 18,000g for 30 min. Peptide concentrations were measured in the supernatant by specific radioimmunoassays (RIAs). In the HT, there were significant (P < 0.05) decreases in ACTH and beta-EP content by 30 hr post-E2B and a significant (P < 0.05) decrease in HT CRH content 48 hr post-E2B. Thereafter, CRH, ACTH, and beta-EP content increased up to 72 hr post-E2B. In the AP, there was an almost linear decrease in the CRH content through 48 hr post-E2B followed by a marked 20-fold (P < 0.01) increase in the AP CRH content at 72 hr post-E2B, which corresponds to the time of the descending arm of the LH surge. The patterns of ACTH and beta-EP content were very similar in the AP, while that of CRH differed markedly. In contrast, in the HT CRH, ACTH, and beta-EP profiles were very similar. Significant (P < 0.05) increases in circulating levels of ACTH, beta-EP, and cortisol were evident at 30 hr (all 3 hormones), 48 hr (beta-EP and cortisol), and 72 hr (cortisol) post-E2B, which corresponds with the time of decreased hypothalamic content of CRH, ACTH, and beta-EP. These results suggest that there maybe a marked activation of the hypothalamo-anterior pituitary-adrenal axis during the negative and positive feedback phases of the E2B-induced LH surge in the ovariectomized monkey”.
[K] KOGA F SUMI S UMEDA H 1997. [A case of concurrent bilateral adrenocortical adenoma causing Cushing's syndrome] Hinyokika Kiyo. 1997 Apr;43(4):275-8. [Article in Japanese] PMID: 9161855 “A 43-year-old woman presented with obesity and lumbago. Endocrinological examinations revealed normal plasma cortisol levels and a suppressed serum adrenocorticotropic hormone (ACTH) level. On venous sampling, markedly elevated plasma cortisol levels were observed for bilateral adrenal veins (243 and 62.3 micrograms/dl on the right and left sides, respectively). Although the computed tomogram revealed bilaterally enlarged adrenal glands, 131I-adosterol scintigram showed a strong uptake only on the right side. Right adrenalectomy successfully relieved Cushing's syndrome. Pathological diagnosis was adrenocortical adenoma, 3.5 cm in diameter. Cushing's syndrome recurred in 9 years. At that time, she underwent left subtotal adrenalectomy including a 3-cm adrenocortical adenoma. Postoperative convalescence has been uneventful with oral steroid supplementation. All 14 previously reported cases of bilateral adrenocortical adenoma (BAA) causing Cushing's syndrome as well as the present case were concurrent and dominant in females of reproductive age. This suggests that some cofactors other than ACTH, such as estrogen, contribute to the pathogenesis of BAA.
[L] VIAU V MEANEY M J 1991. Variations in the hypothalamic-pituitary-adrenal response to stress during the estrous cycle in the rat. Endocrinology. 1991 Nov;129(5):2503-11. doi: 10.1210/endo-129-5-2503. PMID: 1657578 DOI: 10.1210/endo-129-5-2503 “To investigate the role of gonadal steroids in the hypothalamic-pituitary-adrenal (HPA) response to stress, we studied adrenocorticotrophin (ACTH) and corticosterone (B) responses to 20-min restraint stress in cycling female rats, and in ovariectomized (OVX) rats replaced with physiological levels of estradiol (E2) and progesterone (P). In cycling rats, we found significantly higher peak ACTH (P less than 0.01) and B (P less than 0.05) responses to stress during proestrus compared to the estrous and diestrous phases. No differences were found in either basal ACTH and B levels across the cycle phases. In a separate study, OVX rats were maintained on low, physiological levels of E2 and P with silastic implants for 3 days, and injected either with oil (O'), 10 micrograms of E2 (E') 24 h before stress testing, or with E2 and 500 micrograms P 24 and 4 h, respectively, prior to stress (EP'). These treatments mimicked endogenous profiles of E2 and P occurring during diestrous, proestrous, and late proestrous-early estrous phases, respectively. In response to stress, ACTH levels were higher (P less than 0.01) in the E' group compared to the EP' and O' groups. Although the peak B response was similar in all groups, the E' and EP' groups secreted more B after the termination of stress than did the O' group. Within the 20 min stress period, ACTH levels in the E' group were significantly (P less than 0.05) higher at 5, 10, and 15 min after the onset of stress, compared to the EP' and O' groups. Plasma B levels were significantly higher in the E' group at 5 and 10 min (P less than 0.05 and P less than 0.01, respectively) compared to the EP' and O' group. beta-endorphin-like immunoreactive responses to restraint stress were also significantly higher in the E' group compared to the EP' (P less than 0.05) and O' (P less than 0.01) groups. In contrast to the effect seen at 24 h, ACTH responses to stress 48 h after E2 injection in the E' group were comparable to O' animals. There was no effect of E2 on ACTH clearance, whereas B clearance was enhanced in E' treated animals vs. O'-treated animals. These results indicate that the HPA axis in the female rat is most sensitive to stress during proestrous. Such enhanced HPA responses to stress are limited to the early portion of proestrous, as progesterone appears to inhibit the facilitatory effects of estrogen on ACTH release during stress. Taken together, these results suggest an ovarian influence on both activational and inhibitory components of HPA activity.
[M] GONZALEZ F, 2007. Adrenal involvement in polycystic ovary syndrome. Semin Reprod Endocrinol. 1997 May;15(2):137-57. doi: 10.1055/s-2007-1016296. PMID: 9165658 DOI: 10.1055/s-2007-1016296 “The etiology of hyperandrogenic chronic anovulation is heterogeneous and relatively unknown in the majority of cases. Affected individuals in this latter segment are considered to have polycystic ovary syndrome (PCOS) of which 50 to 60% exhibit androgen excess of adrenal origin. An understanding of normal adrenal function provides insight into the factors that contribute to adrenal androgen excess in PCOS. Since pituitary ACTH secretion promotes developmental growth and overall steroidogenic efficiency within the adrenal cortex, it is probable that these actions of ACTH along with the adrenal's unique centripetal circulation play a major role in the induction of adrenarche. This latter phenomenon is characterized by alterations in adrenocortical morphology and steroidogenic enzyme activities culminating in increases in adrenal androgens to normal circulating adult levels. Thus, it is not surprising that adrenal dynamic testing has revealed increased 17,20 lyase activity or adrenal androgen hyper-responsiveness to ACTH as the two abnormalities leading to adrenal androgen excess in PCOS. Whereas 17,20 lyase hyperactivity diagnosed by defined criteria in response to pharmacological ACTH may be an intrinsic genetic defect, increases in 17,20 lyase activity and adrenal androgen hyper-responsiveness to ACTH in response to physiological ACTH may be promoted by the functional elevation of estrogen of ovarian origin in PCOS. The latest in vitro data suggest the estrogen may elicit its effect on the adrenal cortex through a receptor mediated mechanism. Therefore, the currently available data indicate that adrenal androgen excess in PCOS is also heterogeneous in etiology.
[N] ESCOBAR-MORREALE H F SERRANO-GOTARREDONA J, 1997. Mild adrenal and ovarian steroidogenic abnormalities in hirsute women without hyperandrogenemia: does idiopathic hirsutism exist? Metabolism 1997 Aug;46(8):902-7. Escobar-Morreale HF, Serrano-Gotarredona J, Garcia-Robles R, Sancho J, Varela C "Basal and ACTH-stimulated 17OHP and delta 4-A, and stimulated DHEA concentrations were reduced with ovarian suppression, but their net increment and ratio to the increase of F in response to ACTH remained unchanged, reflecting the ovarian contribution to the secretion of these steroids.".
https://doi.org/10.1016/S0026-0495(97)90077-9Get rights and content “To study ovarian and adrenal steroid profiles of women with idiopathic hirsutism, we compared sex steroid and basal and corticotropin (ACTH)-stimulated adrenal steroid levels before and after ovarian suppression induced by a long-acting gonadotropin-releasing hormone agonist analog (GnRH-a) in 24 hirsute women without hyperandrogenemia. Twelve healthy women served as controls for basal and ACTH-stimulated adrenal steroid levels. Serum levels of testosterone (T), sex hormone—binding globulin (SHBG), estradiol (E2), basal and ACTH-stimulated 17-hydroxyprogesterone (17OHP), dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), Δ4-androstenedione (Δ4-A), 11-deoxycortisol (S) and cortisol (F), and basal and luteinizing hormone—releasing hormone (LHRH)-stimulated gonadotropin levels were measured before and 21 days after 3.75 mg intramuscular triptorelin in hirsute women. Basal T levels and basal and ACTH-stimulated Δ4-A, DHEA, and DHEAS levels were not different in hirsute women with respect to controls. Basal and ACTH-stimulated 17OHP was elevated, and decreased to normal after ovarian suppression with triptorelin. Although basal and ACTH-stimulated Δ4-A levels were normal, the ΔgD4-AΔF and ΔgD4-AΔ17OHP ratios were elevated and remained elevated after ovarian suppression, suggesting enhanced adrenal Δ4-17,20-lyase activity. T, F, S, and DHEAS levels were not affected by ovarian suppression. Basal and ACTH-stimulated 17OHP and Δ4-A, and stimulated DHEA concentrations were reduced with ovarian suppression, but their net increment and ratio to the increase of F in response to ACTH remained unchanged, reflecting the ovarian contribution to the secretion of these steroids. We conclude that idiopathic hirsute women with normoandrogenemia show an increase in ovarian secretion of 17OHP and a minimally increased adrenal Δ4-17,20-lyase activity, suggesting that mild forms of ovarian a nd adrenal functional hyperandrogenism may be present in these patients with otherwise unexplained hirsutism”. https://www.sciencedirect.com/science/article/abs/pii/S0026049597900779
[O] SAOUD C J WOOD C E, 1997. Modulation of ovine fetal adrenocorticotropin secretion by androstenedione and 17beta-estradiol. Am J Physiol. 1997 Apr;272(4 Pt 2):R1128-34. doi: 10.1152/ajpregu.1997.272.4.R1128. PMID: 9140011 DOI: 10.1152/ajpregu.1997.272.4.R1128 “Parturition in sheep is initiated by increases in activity of the fetal hypothalamic-pituitary-adrenal axis. We have previously reported that cortisol negative feedback efficacy is decreased at the end of gestation. The present study was designed to test the hypothesis that increasing plasma estrogen and/or androgen concentrations in the fetus might increase plasma adrenocorticotropic hormone (ACTH) concentration, either by stimulating ACTH secretion or by altering the negative feedback effect of cortisol on ACTH. Fetal sheep were chronically catheterized and treated with no steroid (control), 17beta-estradiol, or androstenedione (each approximately 0.24 mg/day). After catheterization and implantation of steroid pellet, fetuses were subjected to two short (10 min) periods of sodium nitroprusside-induced hypotension with or without pretreatment with intravenous infusion of hydrocortisone sodium succinate (0.5 microg/min) to test fetal ACTH responsiveness to stress and cortisol negative feedback efficacy. Estradiol treatment significantly increased basal plasma ACTH and cortisol concentrations relative to control fetuses but did not interfere with the inhibition of ACTH secretion by cortisol. Fetal plasma ACTH responses to hypotension were significantly suppressed approximately 60% in both control and estradiol-treated groups. Androstenedione treatment significantly increased basal fetal plasma ACTH and decreased basal fetal plasma cortisol concentration. Androstenedione did not alter stimulated levels of fetal ACTH but did block the inhibition of stimulated ACTH by cortisol. We conclude that increased fetal cortisol and ACTH secretion at the end of gestation may be due to the combined effects of the gonadal steroids in that estradiol increases basal plasma ACTH secretion while androstenedione reduces cortisol negative feedback efficacy.
[P] LADO-ABEAL J, RODRIGUEZ-ARNAO J, 1998. PMID: 9745407. Menstrual abnormalities in women with Cushing's disease are correlated with hypercortisolemia rather than raised circulating androgen levels. J Clin Endocrinol Metab. 1998 Sep;83(9):3083-8. doi: 10.1210/jcem.83.9.5084. DOI: 10.1210/jcem.83.9.5084 “Menstrual irregularity is a common complaint at presentation in women with Cushing's syndrome, although the etiology has been little studied. We have assessed 45 female patients (median age, 32 yr; range, 16-41 yr) with newly diagnosed pituitary-dependent Cushing's syndrome. Patients were subdivided into 4 groups according to the duration of their menstrual cycle: normal cycles (NC; 26-30 days), oligomenorrhea (OL; 31-120 days), amenorrhea (AM; > 120 days), and polymenorrhea (PM; < 26 days). Blood was taken at 0900 h for measurement of LH, FSH, PRL, testosterone, androstenedione, dehydroepiandrosterone sulfate, estradiol (E2), sex hormone-binding globulin (SHBG), and ACTH; cortisol was sampled at 0900, 1800, and 2400 h. The LH and FSH responses to 100 micrograms GnRH were analyzed in 23 patients. Statistical analysis was performed using the nonparametric Mann-Whitney U and Spearman tests. Only 9 patients had NC (20%), 14 had OL (31.1%), 15 had AM (33.3%), and 4 had PM (8.8%), whereas 3 had variable cycles (6.7%). By group, AM patients had lower serum E2 levels (median, 110 pmol/L) than OL patients (225 pmol/L; P < 0.05) or NC patients (279 pmol/L; P < 0.05), and higher serum cortisol levels at 0900 h (800 vs. 602 and 580 nmol/L, respectively; P < 0.05) and 1800 h (816 vs. 557 and 523 nmol/L, respectively; P < 0.05) and higher mean values from 6 samples obtained through the day (753 vs. 491 and 459 nmol/L, respectively; P < 0.05). For the whole group of patients there was a negative correlation between serum E2 and cortisol at 0900 h (r = -0.50; P < 0.01) and 1800 h (r = -0.56; P < 0.01) and with mean cortisol (r = -0.46; P < 0.05). No significant correlation was found between any serum androgen and E2 or cortisol. The LH response to GnRH was normal in 43.5% of the patients, exaggerated in 52.1%, and decreased in 4.4%, but there were no significant differences among the menstrual groups. No differences were found in any other parameter. In summary, in our study 80% of patients with Cushing's syndrome had menstrual irregularity, and this was most closely related to serum cortisol rather than to circulating androgens. Patients with AM had higher levels of cortisol and lower levels of E2, while the GnRH response was either normal or exaggerated. Our data suggest that the menstrual irregularity in Cushing's disease appears to be the result of hypercortisolemic inhibition of gonadotropin release acting at a hypothalamic level, rather than raised circulating androgen levels.
[Q] DE LEO V MARCA A TALLURI B, 1998. Hypothalamo-pituitary-adrenal axis and adrenal function before and after ovariectomy in premenopausal women. Eur J Endocrinol. 1998 Apr;138(4):430-5. doi: 10.1530/eje.0.1380430. PMID: 9578512
DOI: 10.1530/eje.0.1380430 “The hypothalamo-pituitary-adrenal (HPA) axis is modulated by sex hormones. Few data exist on the relation between acute estrogen deficit and HPA axis response to corticotropin-releasing hormone (CRH). The effects of a sudden drop in estradiol levels on basal and CRH-stimulated levels of ACTH, cortisol, testosterone, androstenedione and 17-hydroxyprogesterone (17-OHP) were assessed in nine premenopausal women (44-48 years of age), before and after ovariectomy. The CRH test was performed before and 8 days after ovariectomy. A significant reduction in ACTH and adrenal steroids but not in cortisol response to CRH was observed after ovariectomy. The ratio of deltamax androstenedione/17-OHP after CRH stimulation was substantially the same before and after ovariectomy, whereas deltamax 17-OHP/cortisol was significantly lower in ovariectomized women showing increased 21- and 11beta-hydroxylase activity. The results show that the acute estrogen deficit induces changes in the HPA axis characterized by reduced stimulated secretion of ACTH and steroids but normal stimulated cortisol production”.
***