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Pharmacological and Integrative Treatment of Stress-Induced Hypothalamic Amenorrhea
Abstract
Among secondary amenorrheas, hypothalamic amenorrhea (HA) is the one with no evidence of endocrine/systemic causal factors. HA is mainly related to various stressors affecting neuroendocrine control of the reproductive axis. In clinical practice, HA is mainly associated with metabolic, physical, or psychological stress. Stress is the adaptive response of our body through all its homeostatic systems, to external and/or internal stimuli that activate specific and nonspecific physiological pathways. HA occurs generally after severe stressed conditions/situations such as dieting, heavy training, or intense emotional events, all situations that can induce amenorrhea with or without body weight loss and HA is a secondary amenorrhea with a diagnosis of exclusion. In fact, the diagnosis is essentially based on a good anamnestic investigation. It has to be investigated using the clinical history of the patient: occurrence of menarche, menstrual cyclicity, time and modality of amenorrhea, and it has to be excluded any endocrine disease or any metabolic (i.e., diabetes) and systemic disorders. It is necessary to identify any stressed situation induced by loss, family or working problems, weight loss or eating disorders, or physical training or agonist activity. Peculiar, though not specific, endocrine investigations might be proposed but no absolute parameter can be proposed since HA is greatly dependent from individual response to stressors and/or the adaptive response to stress. This chapter aims to give insights into diagnosis and putative therapeutic strategies.
... Typically, such hypothalamic dysfunction can occur in all women during fertile life, with no difference between adolescence as well as during adult life [1][2][3]. It is known as functional hypothalamic amenorrhea (FHA), and it is associated with metabolic, physical, or psychological stress (after severe dieting, heavy training, intense emotional events, or a combination of them) [4,5] with or without body weight loss [6]. ...
... Various hormones, neurotransmitters, and neuromodulators are involved in the control of GnRH (PRL, cortisol, opioids, noradrenaline, dopamine, etc.) [4] and various putative treatments have been proposed to restore the activity of the reproductive axis from estroprogestins, estriol [10] to neuroactive compounds such as pivagabine, naltrexone [11,12]. ...
... FHA occurs for the combination of stressors (physical, psychological, and metabolic stressors) and can disrupt ovarian and other endocrine regulation [5,9,18]. All these stressors act on hypothalamic and extra hypothalamic areas inducing specific defensive behavior in the many hypothalamic centers such as those controlling reproduction, body temperature, food intake, sleep regulation [4,15]. The restoration of normal feeding and/or eliminating the main stressors induces the recovery of reproductive function and of the all hypothalamic activities [4]. ...
Functional hypothalamic amenorrhea (FHA) is a relatively frequent disease due to the combination of metabolic, physical, or psychological stressors. It is characterized by the low endogenous GnRH-induced gonadotropin secretion, thus triggering the ovarian blockade and a hypoestrogenic condition. Up to now various therapeutical strategies have been proposed, both using hormonal treatment as well as neuroactive compounds. Since carnitine, namely l-acetyl-carnitine (LAC), has been demonstrated to be effective in the modulation of the central hypothalamic control of GnRH secretion, we aimed to evaluate whether a combined integrative treatment for 12 weeks of LAC (250 mg/die) and l-carnitine (500 mg/die) was effective in improving the endocrine and metabolic pathways in a group of patients (n = 27) with FHA. After the treatment, interval mean LH plasma levels increased while those of cortisol and amylase decreased significantly. When patients were subdivided according to baseline LH levels, only hypo-LH patients showed the significant increase of LH plasma levels and the significant decrease of both cortisol and amylase plasma levels. The increased 17OHP/cortisol ratio, as index of the adrenal activity, demonstrated the reduced stress-induced adrenal activity. In conclusion, our data sustain the hypothesis that the integrative administration of LAC plus l-carnitine reduced both the metabolic and the neuroendocrine impairment of patients with FHA.
... These physical, psychological, and metabolic stressors negatively affect gonadotropin-releasing hormone (GnRH) release and the reproductive axis, activating or inhibiting hypothalamic, and/or extra-hypothalamic areas in brain through neurotransmitters and neuropeptides acting centrally [7]. Various hormones, neurotransmitters, and neuromodulators are involved in the control of GnRH such as prolactin (PRL), cortisol, opioids, noradrenaline, and dopamine [4]. ...
... Various hormones, neurotransmitters, and neuromodulators are involved in the control of GnRH such as prolactin (PRL), cortisol, opioids, noradrenaline, and dopamine [4]. Such negative hypothalamic response is nothing else than a defensive system [7,8]. In primate females, and in human females in particular, an adaptive mechanism during stress is represented by the reduction of reproductive axis activity, blocking a function which is not essential to survive. ...
Purpose:
Functional hypothalamic amenorrhea (FHA) occurs in response to exaggerated stressors with or without body weight loss. Various hormones, neurotransmitters, and neuromodulators are involved in the control of GnRH and kisspeptin is one of them. Our study aimed to evaluate the putative temporal coupling between kisspeptin and GnRH-induced LH pulsatile secretion.
Methods:
In total, 71 patients with FHA were selected for this study. All patients undergo to a pulsatility study for LH and kisspeptin evaluation (120 min, sampling every 10 min), and to an endocrine evaluation for prolactin (PRL), estradiol (E2), androstenedione (A), 17-hydroxy-progesterone (17OHP), TSH, fT3, fT4, insulin, cortisol and testosterone (T), glucose, total cholesterol, triglycerides.
Results:
Our data demonstrated kisspeptin and LH pulsatile secretions and that both hormones are co-secreted and temporally coupled at time 0 (p < 0.05). When patients were subdivided in hypo-LH (≤3 mIU/ml, n = 58) and normo-LH (>3 mIU/ml, n = 13), more insights were observed on the specific correlations of metabolic and hormone profiles with pulsatility indexes of LH and kisspeptin.
Conclusions:
Our study demonstrated the presence of a distinct kisspeptin episodic secretion in patients with FHA, and showed the temporally coupling of kisspeptin with LH secretory episodes thus supporting that though in amenorrhea, the reproductive axis is still relying on kisspeptin to drive GnRH discharge. In addition, correlations among hormonal data sustain the hypothesis that stress-induced compensatory events are the main direct and indirect promoters of the reproductive blockade in patients affected by FHA.
... Secondary amenorrhea is a common condition that is characterized by the lack of a menstrual cycle for at least 3 months and can be related to several clinical situations [1][2][3][4][5]. Typically, Functional Hypothalamic Amenorrhea (FHA) is a kind of amenorrhea that occurs with no concomitant systemic or hormonal diseases [1][2][3][4][6][7][8][9], and it covers up to 35% of cases of secondary amenorrhea [6][7][8]. ...
Background: Functional Hypothalamic Amenorrhea (FHA) is a stress-induced blockade of the reproductive axis. Such impairment is mainly due to altered control of GnRH-induced gonadotropin secretion as well as alterations of other endocrine functions. Methods: Seventeen patients with FHA participated in the study. Basal hormonal profiles and GnRH and Naloxone tests for LH (Luteinizing Hormone) and for LH and cortisol responses, respectively, were performed before and after two weeks of administration of a very low dose of estradiol (2.5 ng two times a day). Results: The treatment improved both gonadotropins, mainly LH. The LH response to the GnRH test improved in terms of the peak amplitude, as evaluated using Instantaneous Secretory Rates (ISR) computation. Moreover, when performing the Naloxone test after the treatment interval, FHA patients showed a quicker LH response and recovery of the cortisol response. Conclusions: Our study supports the relevance of very low dose estradiol priming to promote and restore impaired neuroendocrine function in patients with FHA
... The greatest improvement was registered with the association of treatments with low dose SKA molecules and UV-B treatment which has led to improvements in 92/93. No adverse effects have been reported, and the safety and efficacy of low dose SKA were verified [29], [30], [31]. The randomised, doubleblinded, controlled clinical trial included children with mild to medium IgE-mediated and non-IgE mediated Atopic Dermatitis in an acute phase of the disease was conducted using low dose SKA (IL-12 and IFN-γ). ...
T
The P.N.E.I. (Psycho-Neuro-Endocrine-Immunology) approach is represented by the interdisciplinary concept of bidirectional cross-talk between the psycho-neuro-endocrine and immune systems, which can influence the immune response. The well-known Gut-Brain Axis and the Gut-Skin Axis can be merged in a bigger network- the Gut-Brain-Skin Axis, with complex regulation by cytokines, neuro-peptides, neuro-hormones and another messenger (signalling) molecules and maybe the most important modulator of the Gut-Brain-Skin Axis/ the gut microbiota. The role of gut bacterial homeostasis is very important, and the homeostatic imbalance of the immune response may be a relevant etiologic/pathophysiologic factor for extra-intestinal and intestinal inflammatory, allergic and autoimmune diseases. The Low Dose Cytokines Medicine (LDM) is an innovative therapeutic approach. It is based on the most advanced knowledge in molecular biology and low dose pharmacology with the primary outcome. The SKA (Sequential Kinetic Activation) technology, codified and standardised by GUNA S.p.a. -Italy- makes the low doses of signalling molecules able to be active even below the minimum dose classically considered as effective and the significative efficacy of orally administered low-dose signalling molecules is the most representative aspect of LDM. The Physiologic Nutraceuticals and the Low Dose Medicine are two of the most promising approaches for the treatment of skin diseases based on the rebalance of the immune response and the recovery of gut dysbiosis.
... The greatest improvement was registered with the association of treatments with low dose SKA molecules and UV-B treatment which has led to improvements in 92/93. No adverse effects have been reported, and the safety and efficacy of low dose SKA were verified [29], [30], [31]. The randomised, doubleblinded, controlled clinical trial included children with mild to medium IgE-mediated and non-IgE mediated Atopic Dermatitis in an acute phase of the disease was conducted using low dose SKA (IL-12 and IFN-γ). ...
The P.N.E.I. (Psycho-Neuro-Endocrine-Immunology) approach is represented by the interdisciplinary concept of bidirectional cross-talk between the psycho-neuro-endocrine and immune systems, which can influence the immune response. The well-known Gut-Brain Axis and the Gut-Skin Axis can be merged in a bigger network-the Gut-Brain-Skin Axis, with complex regulation by cytokines, neuro-peptides, neuro-hormones and another messenger (signalling) molecules and maybe the most important modulator of the Gut-Brain-Skin Axis/ the gut microbiota. The role of gut bacterial homeostasis is very important, and the homeostatic imbalance of the immune response may be a relevant etiologic/pathophysiologic factor for extra-intestinal and intestinal inflammatory, allergic and autoimmune diseases. The Low Dose Cytokines Medicine (LDM) is an innovative therapeutic approach. It is based on the most advanced knowledge in molecular biology and low dose pharmacology with the primary outcome. The SKA (Sequential Kinetic Activation) technology, codified and standardised by GUNA S.p.a.-Italy-makes the low doses of signalling molecules able to be active even below the minimum dose classically considered as effective and the significative efficacy of orally administered low-dose signalling molecules is the most representative aspect of LDM. The Physiologic Nutraceuticals and the Low Dose Medicine are two of the most promising approaches for the treatment of skin diseases based on the rebalance of the immune response and the recovery of gut dysbiosis.
Free radical-induced oxidative stress is the root cause of many diseases, such as diabetes, stress and cardiovascular diseases. The objective of this research was to screen GABA levels, antioxidant activities and bioactive compounds in brown rice. In this study, we first fermented brown rice with different lactic acid bacteria (LABs), and the best LAB was selected based on the levels of GABA in the fermentate. Lactobacillus reuterii generated the highest levels of GABA after fermentation. To ascertain whether germination can improve the GABA levels of brown rice, we compared the levels of GABA in raw brown rice (Raw), germinated brown rice (Germ), fermented brown rice (Ferm) and fermented-germinated brown rice (G+F) to identify the best approach. Then, antioxidant activities were investigated for Raw BR, Germ BR, Ferm BR and G+F BR. Antioxidant activity was calculated using a 2,2-diphenyl-1-picryl hydrazile radical assay, 2,2-azino-bis-(3-ethylene benzothiozoline-6-sulfonic acid) radical assay and ferric-reducing antioxidant power. In Ferm BR, DPPH (114.40 ± 0.66), ABTS (130.52 ± 0.97) and FRAP (111.16 ± 1.83) mg Trolox equivalent 100g, dry weight (DW), were observed as the highest among all samples. Total phenolic content (97.13 ± 0.59) and total flavonoids contents (79.62 ± 1.33) mg GAE/100 g and catechin equivalent/100 g, DW, were also found to be highest in fermented BR. Furthermore, an untargeted metabolomics approach using ultra-high-performance liquid tandem chromatography quadrupole time of flight mass spectrometry revealed the abundance of bioactive compounds in fermented BR, such as GABA, tryptophan, coumaric acid, L-ascorbic acid, linoleic acid, β-carotenol, eugenol, 6-gingerol, etc., as well as bioactive peptides which could contribute to the health-promoting properties of L. reuterii fermented brown rice.
The key element of Psycho‐Neuro‐Endocrine‐ Immunology (PNEI) approach is represented by the concept of bidirectional crosstalk between the psychoneuroendocrine and immune systems. The Gut‐Brain‐Skin Axis is a PNEI microcosm that acts as a homeostatic controller not only of its own systems but of the whole organism. Physiological inflammation is overcome by a low‐intensity chronic inflammatory condition called Low Grade Chronic Inflammation (LGCI). LGCI is one of the most important etiopathogenetic factors of the most dramatic dermatologic chronic inflammatory autoimmune diseases, and consequently a therapeutic target. Low‐dose medicine (LDM) is an innovative therapeutic approach based on the most advanced knowledge in molecular biology, PNEI, and research results in the field of low‐dose pharmacology. The use of biological molecules to control and drive the intercellular cross‐talk in order to restore physiological homeostasis is the innovative core of LDM.
The pattern of pulsatile GnRH secretion is abnormal in some women with hypothalamic amenorrhea (HA) consequent to previous exercise or weight loss. Both diminished frequency pulsatile LH secretion, and by inference GnRH secretion, and normal LH pulsatility have been reported. We assessed whether the patterns of GnRH secretion varied with time by measuring plasma LH every 15 or 20 min for 24 h on 1-3 occasions during a 10-month period in 14 women with HA (a total of 24 studies). During the day, mean LH pulse frequency [1.0 +/- 0.1 (+/- SE) pulses/8 h] was lower than that in normal women in the early follicular phase of their cycles (5.1 +/- 0.6), and the frequency in individual HA patients was lower than early follicular phase values in 16 of 17 studies. The slow daytime LH pulse frequency also was a consistent finding, in that the values in repeat studies varied by less than 2 pulses/8 h in all but 1 patient. LH pulse frequency (2.0 +/- 0.4 pulses/8 h) was higher and more variable during sleep, and normal early follicular phase frequencies were found in 20% of patients with HA. The mechanisms whereby GnRH pulse frequency is reduced are not known. alpha-Adrenergic agonist drugs stimulate GnRH pulsatile secretion in rodents, but administration of the alpha 2-agonist clonidine (0.15 mg, orally, at 0800 and 2000 h) did not increase the frequency of LH pulses in 7 women (1.7 +/- 0.4 pulses/8 h). In contrast, administration of naloxone (1 mg/m2 X h, iv) for 8 h during the day to 14 patients, increased LH pulse frequency (3.3 +/- 0.5 pulses/8 h). In 8 of these 14 women, LH pulse frequency (4.9 +/- 0.4 pulses/8 h) increased into the range found during the normal early follicular phase, while in the other 6 women pulse frequency was not significantly increased (1.4 +/- 0.4 pulses/8 h). Plasma estradiol levels were similar in naloxone-responsive and unresponsive women, but spontaneous LH pulse frequency was higher at night in naloxone-responsive patients (2.9 +/- 0.6 vs. 1.4 +/- 0.3 pulses/8 h). The presence of nocturnal LH pulses did not predict responsiveness to naloxone, however, and LH pulse frequency was less than 2 pulses/8 h in 4 of the women who responded to naloxone. These data indicate that slow frequency GnRH secretion is a common finding during the day in women with HA. GnRH secretion is more variable at night, suggesting that the mechanisms involved in reducing pulsatile GnRH secretion are less effective during sleep.(ABSTRACT TRUNCATED AT 400 WORDS)
To evaluate whether the hypothalamus is the site of action of CRF in inhibiting LH levels in female rats, we measured hypophysial-portal blood concentrations of immunoreactive GnRH (irGnRH) after the central injection of CRF. Ovine CRF (0.1, 1.0, 2.0, and 5.0 nmol) was injected intracerebroventricularly to intact rats on the afternoon of proestrus and in long term ovariectomized (OVX) rats in the presence or in absence of estradiol benzoate (OVX + EB). CRF injection decreased the amplitude of the proestrous irGnRH surge without affecting presurge levels. CRF (0.1 nmol) attenuated the afternoon irGnRH surge in OVX + EB rats; higher doses of CRF blocked this surge and decreased nonsurge irGnRH levels. No dose-related alterations of irGnRH levels were observed in OVX rats; only the highest dose of CRF was active. For comparison, plasma LH concentrations were measured after a single dose of CRF (2 nmol) in rats under the same experimental conditions. While CRF decreased LH concentrations in anesthetized proestrous and OVX + EB rats, it was inactive in OVX rats. In contrast, CRF injection in awake rats did decrease LH concentrations in all experimental conditions, suggesting that in OVX rats, the anesthetic (Saffan) used during portal blood collection affected CRF action on LH secretion. Indeed, the observation that the LH response to opiate receptor blockade with naloxone (2.5 mg/kg) in anesthetized OVX rats was different compared to that in awake rats suggested that the ineffectiveness of CRF to decrease irGnRH and LH in OVX anesthetized rats was related to the action of the anesthetic on the opioid system. The existence of a putative CRF-opioid interaction in the inhibitory control of LH secretion was supported by the effectiveness of naloxone to reverse the CRF-induced decrease in LH levels in EB-treated and untreated OVX rats. These results indicate that CRF attenuates LH secretion by a central action to inhibit irGnRH release into the hypophysial-portal circulation and that this action is independent of basal concentrations of irGnRH and/or LH. Moreover, the present results support the involvement of endogenous opioids in mediating the effect of CRF on LH secretion.
We tested the hypothesis that the neuroendocrine control of gonadotropin secretion is altered in certain women distance runners with secondary amenorrhea. To this end, we quantitated the frequency and amplitude of spontaneous pulsatile LH secretion during a 24-h interval in nine such women. The ability of the pituitary gland to release LH normally was assessed by administration of graded bolus doses of GnRH during the subsequent 8 h. Compared to normally menstruating women, six of nine amenorrheic distance runners had a distinct reduction in spontaneous LH pulse frequency, with one, three, six, five, four, or two pulses per 24 h (normal, 8-15 pulses/24 h). This reduction in LH pulse frequency occurred without any significant alterations in plasma concentrations of estradiol and free testosterone or 24-h integrated serum concentrations of LH, FSH, or PRL. Moreover, in long-distance runners, the capacity of the pituitary gland to release LH was normal or accentuated in response to exogenous pulses of GnRH. In the six women athletes with diminished spontaneous LH pulsatility, acute ovarian responsiveness also was normal, since serum estradiol concentrations increased normally in response to the GnRH-induced LH pulses. Although long-distance runners had significantly lower estimated percent body fat compared to control women, specific changes in pulsatile gonadotropin release did not correlate with degree of body leanness. In summary, certain long-distance runners with secondary amenorrhea or severe oligomenorrhea have unambiguously decreased spontaneous LH pulse frequency with intact pituitary responsiveness to GnRH. This neuroendocrine disturbance may be relevant to exercise-associated amenorrhea, since pulsatile LH release is a prerequisite for cyclic ovarian function. We speculate that such alterations in pulsatile LH release in exercising women reflect an adaptive response of the hypothalamic pulse generator controlling the intermittent GnRH signal to the pituitary gland. The basis for amenorrhea in the remaining runners who have normal pulsatile properties of LH release is not known.
Young female ballet dancers attending professional schools or dancing in companies in which thinness is much admired restrict their food intake and are highly active. The unusual eating habits and levels of activity of some of these dancers have been related to lack of menstrual cycles. Amenorrhea and late menarche among girls and women with average activity levels are associated with undernutrition and weight loss in the range of 10 to 15 per cent of the normal weight for height; such weight loss apparently reduces the fat/lean ratio to less than a critical level. The authors report here on 89 young ballet dancers among whom there was a high incidence of primary amenorrhea, secondary amenorrhea, irregular cycles, and delayed menarche - an incidence correlated with excessive thinness.
Objective To evaluate whether the efficacy of naltrexone administration in patients with hypothalamic amenorrhea correlates to the response to an acute naloxone test. Design Thirty patients with hypothalamic amenorrhea associated with weight loss were studied. After naloxone test (4mg in bolus IV) patients were divided in two groups: group A, nonresponsive (n=15) and group B, responsive (n=15). Group A underwent two cycles of hormonal replacement therapy with E 2 patches and medroxyprogesterone acetate. Then all patients were administered naltrexone at the dosage 50mg/d orally for 6months. A third group of 10 amenorrheic patients were treated with oral placebo with the same schedule. Results Plasma gonadal steroid levels increased in all patients and in 24 of 30 patients the menstrual bleeding occurred within 90days from the beginning of treatment. After 6months from naltrexone discontinuation, 18 of 24 patients still showed the occurrence of menstrual cycles. Luteinizing hormone plasma levels and LH pulse amplitude increased after 3months of treatment and remained unchanged 6months after naltrexone suspension. Plasma FSH levels did not show any change in any patient. The body mass index increased after 3months in all patients who menstruated. Patients treated with placebo did not show any significant change in gonadotropins and gonadal steroid plasma levels. Conclusionss The present study supports the efficacy of naltrexone therapy for patients with hypothalamic amenorrhea either responsive or nonresponsive to naloxone test.
The lack of plasma luteinizing hormone (LH) pulsatile pattern or episodic LH secretory bursts during night have been demonstrated in hypothalamic amenorrhea. The availability of both sensitive and specific immunofluorimetric assay and algorithm for pulse detection enabled us to reanalyze the question of whether or not patients with hypothalamic amenorrhea secrete LH in a pulsatile fashion. Seven women with secondary amenorrhea associated with weight loss and four normally cycling women were studied, sampling every 5minutes for 8hours. Control subjects were studied during four different phases of the menstrual cycle. In all amenorrheic patients, a frequent LH pulsatile secretion, with pulses of low amplitude, was found (10.7±1.4 peaks/8h; mean±SEM). The pulse frequency was significantly higher ( P
Objective To define the characteristics of spontaneous GH episodic secretion and the modulatory role of gonadal steroids in patients with hypothalamic amenorrhea associated with weight loss. Design Women were studied for 8 hours, sampling every 10 minutes, and plasma GH levels were measured by RIA. Subjects Fifteen patients with weight-loss-related amenorrhea were studied in baseline conditions. Five out of 15 patients underwent two cycles of hormonal replacement therapy with E 2 patches (100 μ g every 3 days for 24 days) and medroxyprogesterone acetate (MPA) (10 mg/d, from day 12 to day 24). On the second cycle of therapy, the pulsatility study was repeated twice: after only estrogen (day 11) and after E 2 plus progestin (day 22). Four normally cycling women were studied as a reference group during midfollicular and midluteal phases. Results Amenorrheic patients showed mean plasma GH levels similar to healthy women during the follicular phase but significantly lower than those observed during the luteal phase. GH pulse frequency was higher in patients than in controls, whereas pulse amplitude was comparable with the follicular phase but lower during the luteal phase. During the hormonal replacement therapy, when only E 2 was administered, GH pulse frequency decreased, whereas GH integrated plasma concentrations and GH pulse amplitude increased significantly. After MPA and E 2 administration, GH pulse amplitude and GH plasma levels decreased, which was similar to pretreatment condition. Conclusions The present study demonstrated that in amenorrhea associated with weight loss the frequency of GH episodic release is significantly higher than in normally cycling women. Moreover, a different modulatory role of estrogen (increased amplitude) and P (decreased amplitude) on the episodic release of GH in amenorrheic women undergoing a replacement treatment was shown by the present data.
In a random sample of 1,533 girls aged 8-18 years, all except three menstruated by the age of 15. The frequency of menstrual disorders at each age ranged from 10 to 17%, had no tendency to decrease with age, and was independent of the color of hair. Among 1,702 patients aged 12-39 years presenting with menstrual disorders at the Endocrine Clinic, 503 (29.6%) were 12-19 years old (group A) and the remaining 1,199 were 20-39 years of age (group B). However, the first clinical manifestation of the abnormalities in their cycle appeared before the age of 20 in 68% of this entire group. Menstrual disorders occurred immediately after menarche in 59.6% of the patients in group A, primary oligomenorrhea being the most common complaint (35-39%). Hypothalamic derangement was the most common etiology to occur with the same frequency in the two groups (group A: 63.4%, group B: 61.4%). One in 63 young girls (vs. one in 27 in group B) had a pituitary tumor (six prolactinomas, one growth hormone-secreting adenoma, one craniopharyngioma). We concluded that 1) the failure of menses to appear by the age of 15 is extremely rare, 2) the vulnerability of ovarian cyclicity does not change during the maturation of its controlling mechanism after menarche, 3) two of three females up to the age of 39 years with menstrual disorders manifest their anomaly in the cycle before 20 years of age, 4) the sensitivity of hypothalamic centers is the same in the young and the older subjects and is responsible for the greater part of menstrual disorders, 5) the occurrence of a pituitary tumor in young girls with menstrual disorders is not a remote possibility.
Secondary amenorrhea - the absence of menses for three consecutive cycles - affects approximately 3-4% of reproductive age women and infertility - the failure to conceive after 12 months of regular intercourse - affects approximately 6-10%. Neuroendocrine causes of amenorrhea and infertility, including functional hypothalamic amenorrhea and hyperprolactinemia, constitute a majority of these cases.
In this review, we discuss the physiologic, pathophysiologic and iatrogenic causes of amenorrhea and infertility arising from perturbations in the hypothalamic-pituitary-adrenal axis, including potential genetic causes. We focus extensively on the hormonal mechanisms involved in disrupting the hypothalamic-pituitary-ovarian axis.
A thorough understanding of the neuroendocrine causes of amenorrhea and infertility is critical for properly assessing patients presenting with these complaints. Prompt evaluation and treatment are essential in order to prevent loss of bone mass due to hypoestrogenemia and/or to achieve the time-sensitive treatment goal of conception.
Several neuroendocrine disregulations have been demonstrated in patients with hypothalamic amenorrhea, but a definite therapeutic strategy has not yet been found. Since acetyl-1-carnitine (ALC) has been reported to have a specific effect on central cholinergic, serotoninergic, dopaminergic and opioidergic systems, 20 patients with hypothalamic amenorrhea were treated with ALC (2 g/day, per os). Both the clinical efficacy and the endocrine parameters were evaluated after 6 months. The patients were subdivided in two groups according to their LH plasma levels: A) hypogonadotropic: 10 subjects with plasma LH < 3 mlU/ml, and B) normogonadotropic: 10 subjects with plasma LH > 3 mIU/ml. All subjects underwent: 1) a pulsatility study (4 h sampling every 10 min), 2) GnRH test (two bolus injections of 10 mg at time 0 and ±120), 3) TRH test (200 mg). These parameters were evaluated before and after 6 months of ALC administration. The occurrence of a spontaneous menstruation was observed in 6 out of 10 hypogonadotropinemic and in 4 out of 10 normogonadotropinemic patients. Menstrual bleeding occurred between the 3rd and the 6th month of therapy. Major hormonal changes after ALC administration were observed in the hypogonadotropic subjects. They showed a significant increase in baseline plasma LH levels (from 0.9±0.1 to 3.5±0.7 mIU/ml,p
Corticotropin-releasing factor (CRF) plays a role in coordinating endocrine, autonomic, and behavioral responses to stressful stimuli. Benzodiazepines exert many effects which oppose those of CRF, including anxiolysis and suppression of the pituitary-adrenal axis. In the present study, we employed in situ analysis of CRF heteronucleous RNA (hnRNA) and c-fos mRNA to assess stimulus-induced CRF gene transcription rate following stress and its modulation by chlordiazepoxide (CDP). Male albino rats were exposed to restraint stress for 30 min and sacrificed 30 and 120 min after the onset of stress. Either CDP or vehicle was given intraperitoneally 60 min before stress. To determine plasma ACTH levels by immunoradiometric assay, another group of rats was decapitated 10 min after the onset of restraint stress. Restraint stress induced rapidly and significantly c-fos mRNA and CRF hnRNA expression in the PVN at the 30 min time point. Increases in both RNA copies were significantly inhibited by administration of CDP at doses of 5 and 10 mg/kg. CRF mRNA concentrations were increased significantly in the PVN 120 min after stress and again, CDP attenuated significantly these increases in the PVN. The plasma ACTH increase in response to stress was inhibited significantly by CDP administration at every dose tested. CDP did not change CRF mRNA levels in the non-sressed animal. We conclude that the suppression of cellular activities in the PVN following stress by CDP, while not established directly or indirectly, coincides with the inhibition of CRF gene transcription in the PVN, and that CDP inhibits the hypothalamo-pituitary adrenal (HPA) axis through suppression of activation of neurons, CRF gene transcription, and CRF biosynthesis in the PVN.
The aim of this study was to evaluate relationships between emotional state and hypothalamic activity in patients with hypothalamic secondary amenorrhea. Sixty-seven normal weight patients with hypothalamic amenorrhea were submitted to concomitant psychological and LH pulsatility evaluation. Structured clinical interview for anxiety and depressive disorders (DSM III-R) as well as life events investigations (Paykel test) were performed. LH pulses (blood sampling every 10 min for 4 hr) were analyzed through DETECT program and Instantaneous Secretory Rate were computed. Twenty-one patients reporting life events associated to the onset of amenorrhea had LH pulse frequency (2.28 ± 1.10 pulses/4 hr) lower than those without life events (3.40 ± 1.46 p = .007). LH pulses amplitude was lower in patients meeting a DSM III-R (21 cases: 1.22 ± 0.96 mIU/ml) diagnosis than in those without (1.99 ± 1.20 p = .04) diagnosis. Plasma estradiol and FSH levels as well as duration of amenorrhea and Body Mass Index were similar among groups. It is concluded that psychogenic factors (namely the presence of life events related to the onset of menstrual disorder) are associated with significant and specific changes of hypothalamic activity which could be involved in determining hypogonadism.
To evaluate the relationship between stressful life events and the onset of secondary amenorrhoea Paykel's semi-structured interview for Recent Life Events was administered to patients affected by secondary amenorrhea and also to healthy volunteers.The number, quality, and objective negative impact of life events were compared among different hormonal subtypes of secondary amenorrhoea and healthy normally menstruating women, as a control group.The number of life events in amenorrhoeic patients (N=131) was significantly greater than those observed in the control group (N=64) (45.9 vs 32.8%). Moreover, where only hypothalamic hypogonadotrophic amenorrhoea was considered, the occurrence of life events was significantly higher (59.8%) than in hyperandrogenic (26.6%) or in normogonadotrophic (20.4%) patients. The most prevalent events among hypothalamic hypogonadotrophic amenorrhoeic patients were those classified as ‘undesirable’, ‘uncontrolled’ and with ‘Objective Negative Impact’.The present study supports the hypothesis of a cause-effect relationship between stressful personal life events and the onset of secondary amenorrhoea of hypogonadotrophic subtype.
To evaluate the influence of estriol administration on the hypothalamus-pituitary function and gonadotropins secretion in patients affected by functional hypothalamic amenorrhea (FHA).
Controlled clinical study.
Patients with FHA in a clinical research environment.
Twelve hypogonadotropic patients affected by FHA.
Pulsatility study of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), and a gonadotropin-releasing hormone (GnRH) test (10 μg in bolus) at baseline condition and after 8 weeks of therapy with 2 mg/day of estriol.
Measurements of plasma LH, FSH, estradiol (E(2)), androstenedione (A), 17α-hydroxyprogesterone (17-OHP), cortisol, androstenedione (A), testosterone (T), thyroid-stimulating hormone (TSH), free triiodothyronine (fT(3)), free thyroxine (fT(4)), and insulin, and pulse detection.
After treatment, the FHA patients showed a statistically significant increase of LH plasma levels (from 0.7 ± 0.1 mIU/mL to 3.5 ± 0.3 mIU/mL) and a statistically significant increase of LH pulse amplitude with no changes in LH pulse frequency. In addition, the LH response to the GnRH bolus was a statistically significant increase.
Estriol administration induced the increase of LH plasma levels in FHA and improved GnRH-induced LH secretion. These findings suggest that estriol administration modulates the neuroendocrine control of the hypothalamus-pituitary unit and induces the recovery of LH synthesis and secretion in hypogonadotropic patients with FHA.
Hypothalamic amenorrhea (HA) is characterized by neuroendocrine impairment that, in turn, negatively modulates endocrine function, mainly within the reproductive axis. HA presents with hypo-LH, hypoestrogenism and, until now, a definite therapeutic strategy has not yet been found. The aim of the following study was to test the efficacy of acetyl-L-carnitine (ALC) administration in HA-affected subjects.
Twenty-four patients affected by stress-induced HA were divided into two groups according to LH plasma levels: group A, hypo-LH (LH≤3 mIU/ml; no.=16), and group B, normo-LH (LH>3 mIU/ml; no.=8), were treated with ALC (1 g/day, per os) for 16 weeks.
Patients underwent baseline hormonal assessment, pulsatility test (for LH and FSH), naloxone test (for LH, FSH and cortisol) both before and after 16 weeks of treatment.
Under ALC administration hypo-LH patients showed a significant increase in LH plasma levels (from 1.4±0.3 to 3.1±0.5 mIU/ml, p<0.01) and in LH pulse amplitude (p<0.001). No changes were observed in the normo-LH group. LH response to naloxone was restored under ALC therapy. Maximal LH response and area under the curve under naloxone were significantly increased (p<0.05 and p<0.01, respectively). No changes were observed in the normo-LH patients.
Our data support the hypothesis of a specific role of ALC on counteracting the stress-induced abnormalities in hypo-LH patients affected by hypothalamic amenorrhea.
The effects of epimestrol (5 mg every 6 hours for 5 days) on basal levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (Prl), estradiol, progesterone, and dehydroepiandrosterone sulfate, and on the response to LH-releasing hormone (LH-RH) and thyrotropin-releasing hormone (TRH) stimulation, were studied in 18 cases of secondary amenorrhea and oligomenorrhea of hypothalamic-pituitary origin, in three cases of anorexia nervosa, in two cases of long-lasting progestin-induced amenorrhea, and in one case of precocious menopause. The results in the first 18 patients indicate that epimestrol treatment induces a significant increase in LH and Prl levels after 24 hours, while the FSH increase becomes significant only after 4 days of therapy. Twelve hours after discontinuation of treatment, all three hormone levels decreased significantly to values similar to the basal levels, while the pituitary response to LH-RH indicated a much more marked LH secretion than before treatment. A second test, performed 36 hours after the last drug administration, again showed a significantly higher LH response than that found under basal conditions. No significant variations were observed in the FSH response to LH-RH, nor in the Prl response to TRH. These data suggest that epimestrol interferes at the level of the centers responsible for Prl and gonadotropin secretion in the manner of a weak estrogen.
We tested hypothalamic, pituitary and endocrine function in 19 patients with secondary amenorrhea associated with simple weight loss who did not have anorexia nervosa to evaluate the effects of weight loss on these systems. Thermoregulation at 10 degrees C and 49 degrees C was abnormal and correlated with the percentage below ideal body weight (r = 0.62, P less than 0.02, and r = 0.55, P less than 0.05, respectively). Partial diabetes insipidus was found in 27 per cent of patients with simple weight loss. They had delayed peak plasma luteinizing hormone levels after 10 microgram of luteinizing-hormone-releasing factor, which was correlated with percentage below ideal body weight (r = 0.49, P less than 0.05). Delayed peak plasma thyrotropin levels after 500 microgram of thyrotropin-releasing factor were found. No prolactin, pituitary, thyroid or adrenal abnormalities were present. These findings are qualitatively similar to results of studies in 29 patients with anorexia nervosa, but less severe and less frequently present. We conclude that hypothalamic dysfunction may be caused by weight loss per se.
The gamma-NH2 function of GABA was blocked with either benzoyl group (BG1) or a pivaloyl (timethylacetyl) group (PG2). The two derivatives of GABA obtained by the synthetic procedure were chemically pure and fully characterized. Both 14C-BG1 and 14C-PG2, unlike 14-C-GABA, are able to penetrate the blood-brain barrier in rats after subcutaneous injection. BG1 reached its highest concentration in brain 5 min after injection and PG2 after 30 min. This difference appears to be related to the different hydrophobic character of the two compounds, measured after experiments of partition in a water ethylacetate system, and to the different rate of diffusion following subcutaneous administration. BG1 abolished pentetrazole- and bicuculine-induced convulsions in rat when injected 5 min before the administration of the convulsants and PG2 had similar effects when injected 30 min before convulsants. BG1 and PG2 had a slight inhibitory effect on GAD and both BG1 and PG2 acted as substrates for the action of proteolytic enzymes that convert the two compounds back to GABA. Toxicity of both BG1 and PG2 was practically undetectable in rat following administration of the compounds up to 1 g/kg. Glutamate oxidation by rat brain mitochondria was not affected by either BG1 or PG2.
To determine whether short periods of fasting can suppress the activity of the reproductive axis in normal healthy men, eight men were studied on a fed day and again after 48 h of fasting. Subjects were between 20-32 yr of age and ranged from 84-119% of normal body weight. Blood samples were collected on day 1 (a fed day) and day 3 (after 48 h of fasting) at 15-min intervals from 0800-1600 h through indwelling venous catheters. Fasting for 48 h resulted in a significant decrease in mean LH, FSH, and testosterone concentrations. The mean LH concentration decreased from 2.94 +/- 0.59 IU/L on the fed day to 1.07 +/- 0.14 IU/L after 48 h of fasting, and there was an accompanying decrease in LH pulse frequency (from 5.13 +/- 0.29 to 2.63 +/- 0.62 pulses/8 h) and mean baseline LH concentration (from 1.83 +/- 0.52 to 0.51 +/- 0.07 IU/L), but no significant decrease in LH pulse amplitude. In a second study, blood samples were collected from five subjects who were allowed to eat normally between days 1 and 3; these individuals showed no difference in LH secretion. To begin to examine the possibility that an activation of the hypothalamic-pituitary-adrenal axis leads to the suppression of reproductive hormone levels that occurred after 48 h of fasting, cortisol levels were measured in all plasma samples. There was no significant difference in mean cortisol concentrations on fed vs. fasted days or when cortisol concentrations were examined as hourly means across the 2 days. These results indicate that activity of the reproductive axis can be suppressed in normal healthy men by 48 h of fasting. It appears unlikely that activation of the adrenal axis is the cause of this suppression of reproductive axis activity.
Benzodiazepines produce their pharmacological effects by regulating the interaction of GABA with its recognition site on the GABAA receptor complex. In fact, the anxiolytic effect of benzodiazepines may be considered the consequence of the activation of the GABAA receptors induced by these drugs. On the contrary, beta-carboline derivatives which bind with high affinity to benzodiazepine recognition sites modulate the GABAergic transmission in a manner opposite to that of benzodiazepines. Thus, these compounds reduce the function of the GABA-coupled chloride channel and produce pharmacological effects (anxiogenic, proconvulsant and convulsant) opposite to those of benzodiazepines. Taken together, these data strongly indicate that the GABAA receptor complex plays a major role in the pharmacology, neurochemistry and physiopathology of stress and anxiety. This conclusion is further supported by the finding that the function of the GABAA/benzodiazepine receptor complex may be modified by the emotional state of the animals before sacrifice. Accordingly, using an unstressed animal model, the 'handling-habituated' rats, it has been demonstrated that stress, like anxiogenic drugs, decreases the function of GABAA receptor complex, an effect mimicked by the in vivo administration of different inhibitors of GABAergic transmission and antagonized by anxiolytic benzodiazepines. Moreover, a long-lasting down regulation of GABAergic synapses can be obtained after repeated administration of anxiogenic, proconvulsant and convulsant negative modulators of GABAergic transmission. The latter finding further suggests that GABAergic synapses undergo rapid and persistent plastic changes when the GABAergic transmission is persistently inhibited. Finally, the evidence that the activity of mesocortical dopaminergic pathways is altered in opposite manner by drugs that either inhibit or enhance the GABAergic transmission indicates that GABA has a functional role in regulation of dopaminergic neurons in the rat cerebral cortex. Altogether these results suggest that cortical GABAergic and dopaminergic transmission play a major role in the pharmacology, neurochemistry and pathology of the emotional states and fear.
To determine whether signals occurring during the early stages of undernutrition can have a suppressive effect on the central drive to the reproductive axis, the effects of 1 day of fasting on pulsatile LH and testosterone secretion were examined in adult male rhesus monkeys. Monkeys were maintained with chronic indwelling venous catheters on tether/swivel systems. One day of fasting caused a small weight loss of 0.1-0.2 kg, which represented a loss of 1-3% of the initial body weight. On a day of normal feeding monkeys showed a mean of 4.57 +/- 0.53 LH pulses/12 h (measured from 1900-0700 h). On a subsequent day of fasting LH pulse frequency was significantly reduced to 1.86 +/- 0.46 pulses/12 h (P less than or equal to 0.05). Likewise, there was a similar decrease in testosterone pulse frequency on a day of fasting. The substantial decrease in LH/testosterone pulse frequency was not caused by the intensive blood-sampling regimen, in that collection of blood samples for 12 h on 2 consecutive days of normal feeding did not result in a decrease in either LH or testosterone pulse frequency. Administration of exogenous GnRH in doses of 0.05-0.3 microgram/kg caused LH pulses of similar magnitudes on a day of normal feeding and a day of fasting, suggesting that the decrease in LH pulse frequency during the day of fasting reflects a decrease in GnRH stimulation of the pituitary rather than a loss of pituitary sensitivity to GnRH. Measurement of pulsatile LH across 3 consecutive days (e.g. a day of normal feeding, a day of fasting, and a day of refeeding) indicated that LH pulse frequency is slow before the time that the meal is missed on the second day and remains low throughout the day of fasting (normal feeding, 7 +/- 1.16 pulses/24 h; fasting, 3.33 +/- 0.33 pulses/24 h). Refeeding a normal meal at 1100 h on the third day resulted in an immediate and sustained increase in pulsatile LH secretion above normal frequency (11.07 +/- 0.33 pulses/24 h). These results indicate that very brief periods of undernutrition can significantly suppress the central drive to the reproductive axis in male rhesus monkeys, and this suppression can be rapidly reversed by refeeding. These findings argue against the hypothesis that undernutrition only suppresses central drive to the reproductive axis once a substantial amount of body weight has been lost.
The possible presence of LH pulsatile secretion has been studied in patients with hypothalamic amenorrhea [LH plasma levels, less than 3 (n = 35) or greater than 3 IU/L (n = 18)], amenorrhea associated with hyperandrogenemia (n = 31), or hyperprolactinemia (n = 10). Patients were sampled every 10 min for 4 h, and LH plasma concentrations were determined by the use of an immunofluorimetric assay. The program Detect was used for both pulse detection and data deconvolution, i.e. for instantaneous secretory rate computation, on LH time series. The presence of episodic LH secretion was observed in all patients, and LH pulse frequency ranged between 3.5 +/- 0.3 and 3.8 +/- 0.2 peaks/4 h among the four groups. LH pulse amplitude was significantly reduced in patients affected by hypothalamic amenorrhea with LH plasma levels lower than 3 IU/L (0.7 +/- 0.1 IU/L; P less than 0.01) and significantly increased in patients with hyperandrogenic amenorrhea (6.8 +/- 0.3 IU/L; P less than 0.01) compared to levels in the other groups under study. Instantaneous secretory rate computation permitted the optimal resolution of the secretory events and demonstrated that the duration of gonadotrope secretory bursts ranged from 22.8 +/- 1.4 to 26.8 +/- 2.3 min in amenorrheic patients and did not depend on LH, PRL, or sex steroid plasma levels. In conclusion, the present study shows the presence of significant LH pulsatile release in amenorrheic patients, suggesting that in amenorrheic, as in normally cycling, women the secretory bursts from the gonadotropes have the same duration, despite the plasma LH, PRL, or steroid hormone levels.
Fifteen young women with a diagnosis of secondary hypothalamic amenorrhea of at least 2 years' duration were given either 50 mg naltrexone daily or placebo, following a randomized double-blind crossover scheme. Seven patients did not menstruate with either therapy. In the other eight, the following results were recorded (mean +/- SD and range): a cycle length of 28.7 +/- 7.6 (12-45) days for naltrexone compared with 30.8 +/- 5.9 (16-43) days for placebo, a follicular phase length of 20.8 +/- 5.4 (14-34) days for naltrexone and 23.2 +/- 4.3 (19-32) days for naltrexone and 8.3 +/- 1.6 (5-10) days for placebo. The number of ovulatory cycles was 18 of 24 (75%) with naltrexone and eight of 24 (33%) with placebo (P less than .05). Most luteal phases were short. In five normally menstruating women, we gave either naltrexone or placebo in the luteal phase using a crossover blinded scheme. Steroidogenesis in the normal luteal phase was not impaired by naltrexone therapy. In functional hypothalamic amenorrheic patients with normal weight, menstruation might be restored by either placebo or naltrexone, but naltrexone provides a clinical and therapeutic advantage by increasing the ovulation rate.
We report here a study of the effects of alprazolam on in vivo pituitary-adrenal function in jacketed nonrestrained nonhuman primates and on in vitro CRH release from rat hypothalami and ACTH release from rat dispersed anterior pituicytes. We undertook this study because alprazolam is the only benzodiazepine effective in treating both major depressive and anxiety disorders, and recent data suggest that the hypercortisolism of major depression reflects hypersecretion of CRH. Moreover, the intracerebroventricular administration of CRH can reproduce many of the components of the symptom complex of major depression, including not only hypercortisolism, but also hypothalamic hypogonadism, decreased libido, anorexia, and intense anxiety. As a comparison, we also assessed the effects of diazepam on in vitro CRH release, because in contrast to alprazolam, diazepam is effective in anxiety states but not in depression. Alprazolam (0.01-0.3 mg/kg, iv) produced a dose-dependent inhibition of both plasma ACTH and cortisol secretion in non-restrained adult male rhesus monkeys. Our in vitro studies showed that alprazolam significantly inhibited serotonin (5HT)-induced CRH release in a dose-dependent fashion (10(-10)-10(-5) M). Diazepam also inhibited 5HT-induced CRH release, but was 40 times less potent than alprazolam. Alprazolam was ineffective in blocking basal or CRH-induced ACTH release from rat dispersed anterior pituicytes, suggesting that its in vivo effects are through inhibition of CRH secretion. As expected, the inactive benzodiazepine ligand Ro 15-1788 inhibited the effects of alprazolam on 5HT-induced CRH release, but this occurred only at doses below 10(-7) M. Interestingly, when incubated alone in higher doses with our rat hypothalamic organ culture, Ro 15-1788, like alprazolam, produced a dose-dependent inhibition of 5HT-induced CRH release (10(-7)-10(-5) M), suggesting an agonistic action of Ro 15-1788 at the benzodiazepine receptor at higher concentrations. We conclude that alprazolam is capable of suppressing the primate pituitary-adrenal axis, and that this suppression most likely reflects suppression of the CRH neuron rather than of the pituitary corticotroph cell. We speculate that the enhanced capacity of alprazolam to suppress the CRH neuron relative to other benzodiazepines may contribute to its unique efficacy among this class of drugs in the treatment of major depression. The capacity of Ro 15-1788 to reverse alprazolam-induced suppression of the CRH neuron indicates that the effects of alprazolam are mediated at least in part via its interaction with the benzodiazepine component of the gamma-aminobutyric acidA macromolecular complex.
It is well known that stress in a number of forms induces the secretion of prolactin (PRL) in a number of species. What is not well known is that under certain conditions stress will also induce a decrease in PRL secretion. The conditions whereby stress decreases PRL are those where PRL secretion is elevated such as during the proestrous afternoon surge and during the nocturnal surge of pseudopregnancy. The physiologic significance of the stress-induced increase of PRL is suggested to be important in maintaining the competence of the immune system. The significance of the stress-induced decrease of PRL does not appear to have a major consequence on the physiology of reproduction in the rat and it is suggested that future studies be directed towards its significance in the immune system. The literature is reviewed dealing with the regulation of PRL secretion with emphasis on the factors that generate PRL surges in the rat. In addition the mechanism(s) of the stress-induced increase and decrease is (are) also examined. A hypothesis is presented suggesting an interaction between tuberoinfundibular dopamine secretion and a hypothalamic prolactin releasing factor in the generation of PRL surges and the differential effects of stress on PRL secretion.
Recent studies in the rat have shown that intracerebroventricular administration of CRH inhibited spontaneous pulsatile GH secretion and prevented GH-releasing hormone (GHRH)-induced GH release. We have studied the effect of CRH on GHRH-induced GH release in man. In the first study, CRH was injected iv at three different doses (100, 50, or 25 μg) at 0800 h together with 50 μg GHRH in six men and six women. In a second study, 100 μg CRH were given iv at 0800 h, 1 h before the administration of 50 μg GHRH in five men and five women. Each subject demonstrated a normal GH response after the administration of 50 μg GHRH plus saline. All doses of CRH administered simultaneously with GHRH significantly inhibited GHRH-induced GH release in women [peak value ± SE after GHRH plus saline, 28.9 ± 2.9 μg/L; after GHRH plus 100 μg CRH 9.9 ± 0.7 μg/L (P <0.001); after GHRH plus 50 μg CRH, 8.7 ± 0.8 μg/L (P <0.001); after GHRH plus 25 μg CRH, 9.5 ± 1.6 μg/L (P <0.001)]. In contrast, in men, whil a dose of 100 μg CRH was capable of suppressing GHRH-induced GH secretion (peak value ± SE, 8.1 ± 0.6 vs. 20 ± 2.9 μg/L; P <0.001), no inhibition was observed after 50- and 25-μg doses. When 100 μg CRH were injected 1 h before the administration of 50 μg GHRH, it strongly inhibited GHRH-induced Gh secretion in both men (peak value ± SE, 6.2 ± 2.8 vs. 24.6 ± 5.9 μg/L; P <0.02) and women (peak value ± SE, 14.2 ± 4.5 vs. 37.8 ± 6.7 μg/L; P <0.005), and this inhibition lasted up to 2 h post-CRH administration. These results demonstrate that CRH is capable of inhibiting GHRH-induced GH release in both men and women. Furthermore, the findings suggest that a sexual dimorphism in the neuroregulation of GH secretion may be present in man. In view of the inhibitory action of CRH on GH secretion, simultaneous administration of CRh and GHRH for testing should be avoided in clinical practice.
The lack of plasma luteinizing hormone (LH) pulsatile pattern or episodic LH secretory bursts during night have been demonstrated in hypothalamic amenorrhea. The availability of both sensitive and specific immunofluorimetric assay and algorithm for pulse detection enabled us to reanalyze the question of whether or not patients with hypothalamic amenorrhea secrete LH in a pulsatile fashion. Seven women with secondary amenorrhea associated with weight loss and four normally cycling women were studied, sampling every 5 minutes for 8 hours. Control subjects were studied during four different phases of the menstrual cycle. In all amenorrheic patients, a frequent LH pulsatile secretion, with pulses of low amplitude, was found (10.7 +/- 1.4 peaks/8 h; mean +/- SEM). The pulse frequency was significantly higher (P less than 0.05) than any phases of the control group (early follicular: 7 +/- 0.4 peaks/8 h; late follicular: 6.8 +/- 0.6 peaks/8 h; early luteal: 4.3 +/- 0.4 peaks/8 h; late luteal: 7 +/- 0.3 peaks/8 h). The LH pulsatile release in amenorrheic patients showed a mean pulse duration and amplitude shorter than in any phase of the menstrual cycle of the controls. In conclusion, in weight-loss-related-amenorrhea, the major change was not the absence of the LH pulsatile release but its increased frequency with reduced pulse amplitude.
To further elucidate the neuroendocrine regulation of anterior pituitary function in women with functional hypothalamic amenorrhea (FHA), we measured serum LH, FSH, cortisol, GH, PRL, TSH concentrations simultaneously at frequent intervals for 24 h in 10 women with FHA and in 10 normal women in the early follicular phase (NC). Using the same data, we separately analyzed the cortisol-PRL responses to meals in these women. In addition, the pituitary responses to the simultaneous administration of GnRH, CRH, GHRH, and TRH were assessed in 6 FHA and 6 normal women. The 24-h secretory pattern of each hormone except TSH was altered in the women with FHA. Compared to normal women, the women with FHA had a 53% reduction in LH pulse frequency (P less than 0.0001) and an increase in the mean LH interpulse interval (P less than 0.01); LH pulse amplitude was similar. The 24-h integrated LH and FSH concentrations were reduced 30% (P = 0.01) and 19% (P less than 0.05), respectively. The mean cortisol pulse frequency, amplitude, interpulse interval, and duration were similar in the two groups, but integrated 24-h cortisol secretion was 17% higher in the women with FHA (P less than 0.05). This increase was greatest from 0800-1600 h, but also was present from 2400-0800 h. Cortisol levels were similar in the two groups from 1600-2400 h, resulting in an amplified circadian excursion. In contrast, the 24-h serum PRL levels were markedly lower at all times (P less than 0.0001), the sleep-associated nocturnal elevation of PRL was proportionately greater (P less than 0.05), and serum GH levels were increased at night in the women with FHA (P less than 0.05). Although 24-h serum TSH levels were similar at all times, T3 (P less than 0.05) and T4 (P less than 0.01) levels were lower in the FHA women. The responses of serum cortisol to lunch (P less than 0.01) and dinner (P less than 0.05) and those of serum PRL to lunch (P less than 0.05) and dinner (P = 0.08) were blunted in the women with FHA. Pituitary hormone increments in response to the simultaneous iv administration of GnRH, CRH, GHRH, and TRH were similar in the two groups, except for a blunted PRL response to TRH in the women with FHA (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Because endogenous opioid peptides (EOP) and CRF are activated during stress and decrease LH levels when injected centrally, we have explored the roles of these peptides in the stress-induced inhibition of LH secretion. Three opioid peptide systems [i.e. endorphin (END), enkephalin, dynorphin (DYN)], are present in the hypothalamus, acting on different opiate receptor subtypes (i.e. mu, delta, kappa). We first evaluated which EOP might be involved in the stress-induced decrease of LH levels. Immunoneutralization of EOP and pharmacological blockade of opiate receptors were used to reverse the decrease in LH induced by inescapable intermittent footshock in castrated male rats. Anti-beta-END and anti-DYN-A serum (intracerebroventricularly [icv]) or pretreatment with beta-END antagonist, beta-human END-(6-31) (2 and 5 nmol, icv), or with kappa-antagonists, Mr1452 MS and Mr2266 BS (10 mg/kg BW, ip), reversed electroshock-induced decrease in LH concentrations. beta-funaltrexamine (beta-FNA), an irreversible mu 1-opiate receptor antagonist, was partially effective in blocking the inhibitory effect of stress on LH levels. Neither passive immunization with anti-enkephalin nor the pretreatment with the delta-opiate receptor antagonist, ICI 154,129, (10 and 100 nmol, icv) modified the effect of stress. We then evaluated which endogenous opioid ligands and/or receptors might mediate the inhibitory effect on LH levels of 2 nmol ovine CRF injected icv. Anti-beta-END serum and beta-human END-(6-31), reversed the CRF-induced decrease of LH concentrations, whereas beta-FNA was only partially active. Anti-DYN-A and anti-ENK serum, kappa- and delta-antagonists did not prevent the decline of LH levels in rats receiving CRF centrally. These data suggest that stress-induced inhibition of LH secretion involves the stimulation of beta-END and DYN-A systems via mu/epsilon- or kappa-opiate receptors and that the decrease in circulating LH levels induced by centrally administered CRF may be mediated by the activation of beta-END system. Therefore, it is possible that the activation of the central CRF/beta-END pathway may play an important role in the stress-induced inhibition of reproductive functions.
The effect of foot-shock stress on t-[35S]butylbicyclophosphorothionate [( 35S]TBPS) binding to fresh unwashed membrane preparations from rat cerebral cortex was studied and was compared to those of GABAA receptor agonists and antagonists and to positive and negative modulators of the GABAergic transmission. [35S]TBPS binding was increased in the cerebral cortex of rats exposed to foot shock compared to that of nonstressed rats. Scatchard analysis revealed that the effect of foot shock was due to an increase in the total number of [35S]TBPS binding sites. In contrast, the in vitro addition of muscimol or GABA induced a dose-dependent inhibition of [35S]TBPS binding, an effect abolished by the concomitant addition of the GABA receptor antagonist, bicuculline, which, per se, enhanced [35S]TBPS binding by 73%. Thus, bicuculline, similar to stress, increased [35S]TBPS binding in the same membrane preparation. In contrast to stress, the anxiolytic and positive modulators of the GABAergic transmission (ZK 93423, ZK 91296, and diazepam) inhibited the specific binding of [35S]TBPS in a concentration-dependent manner. The greatest inhibitory effect was produced by ZK 93423 at 30 microM (31% of control), followed by diazepam (54% of control) and by the partial agonist ZK 91296 (61% of control). Scatchard plot analysis indicated that the inhibition induced by ZK 93423 and diazepam was due to a decrease in the density of [35S]TBPS recognition sites. On the other hand, the anxiogenic beta-carbolines DMCM and FG 7142 mimicked the effect of stress. Thus, at a 10 microM concentration, DMCM and FG 7142 increased [35S]TBPS binding by 22% and 26%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
In the adult castrated male rat, exposure to inescapable, intermittent electroshocks inhibited the pulsatile pattern of luteinizing
hormone release and markedly lowered its plasma concentrations. The central administration of the corticotropin-releasing
factor (CRF) antagonist alpha-helical ovine CRF residues 9 to 41 reversed the inhibitory action of stress. Neither its peripheral
injection, nor the intraventricular injection of the inactive CRF analog des-Glu to Arg ovine CRF was effective. These results
suggest that endogenous CRF may mediate some deleterious effects of noxious stimuli on reproduction.
The effects of corticosterone (B) on pituitary responsiveness to LHRH and on gonadal steroid modulation of gonadotropin secretion were investigated using primary cultures of rat pituitary cells. Cultures were treated for 2 days with steroids and then challenged with LHRH for 4 h. B inhibited LH secretion, increasing the EC50 for LHRH from 1.40 to 4.96 nM. The reduction in LH release was accompanied by an increase in cell LH, so that the total amount of LH present in the cultures was unchanged. The EC50 for the effect of B on LH secretion was 0.57 microM. B increased the total amount of FSH present in the cultures. At high concentrations of B (10-100 microM), this effect was associated with an increase in FSH secretion. Testosterone inhibited LH secretion in both the absence and the presence of B. B had no effect in the presence of maximal concentrations of testosterone but augmented the inhibitory effect of lower concentrations. Estradiol (E) stimulated LH secretion in both the absence and the presence of B. However, the stimulatory effect of E was reduced by B, so that cultures treated with both B and E secreted no more LH than untreated cultures. B inhibited the LH secretory responses to Ca2+ influx and protein kinase C activation but did not affect the response to arachidonic acid, suggesting that the mechanism of B action may involve an inhibition of arachidonic acid release. Together these results indicate that the inhibitory effects of stress on reproduction are mediated at least partially by the inhibitory effects of B on LH secretion.
The factors influencing menstrual function in women with low body weight may be complex and are rarely the sole consequence of changes in body weight. Rather, current evidence suggests that a combination of physical, psychological, and nutritional stresses may act additively in the determination of the timing of onset and rate of pubertal progression, menstrual function, and fertility. Many questions remain about the relationship of obesity to ovulatory dysfunction. The fact that most obese women remain fertile suggests that obesity per se is not the sole explanation for the disordered menstrual function and fertility in some obese women. Current evidence suggests the existence of a more complex pathophysiologic mechanism involving changes in sex hormone-binding globulin, altered ovarian and adrenal androgen production, changes in peripheral aromatization of androgens to estrogen, and inappropriate gonadotropin secretion. These hormonal abnormalities of obese women will be summarized subsequently, however, the interested reader is referred to a more detailed review by Friedman and Kim.
With the aim of examining central opioid influences on the control of luteinizing hormone (LH) secretion, we evaluated the LH response to naloxone, an opioid receptor antagonist, in patients affected by normo-, hyper-, and hypogonadotropic amenorrhea, polycystic ovarian disease and hyperprolactinemia. The results indicate that opioid influences are altered in well-defined pathologic conditions (hyperprolactinemia, obesity), in addition to being modified by gonadal steroids.
Weight loss causes loss of menstrual function (amenorrhea) and weight gain restores menstrual cycles. A minimal weight for height necessary for the onset of or the restoration of menstrual cycles in cases of primary or secondary amenorrhea due to undernutrition is indicated by an index of fatness of normal girls at menarche and at age 18 years, respectively. Amenorrheic patients of ages 16 years and over resume menstrual cycles after weight gain at a heavier weight for a particular height than is found at menarche. Girls become relatively and absolutely fatter from menarche to age 18 years. The data suggest that a minimum level of stored, easily mobilized energy is necessary for ovulation and menstrual cycles in the human female.
To evaluate whether ovarian steroid environment may modify endogenous opioid activity at hypothalamic-pituitary level, the effects of naloxone infusion (1.2 mg/h for 4 h) on gonadotropin secretion were studied in 5 postmenopausal women who had natural menopause 3-5 years before the study. In addition, naloxone infusion was repeated in the same subjects after chronic oral treatment with conjugated estrogens (1.25 mg/day in two divided doses for 20 days). Before treatment, both the circulating levels of estrogens and plasma gonadotropins were in the normal range for postmenopausal women and naloxone infusion did not induce any significant modification of gonadotropin secretion. In contrast, after estrogen therapy, and the consequent rise in estrogen plasma levels, naloxone infusion induced a significant LH increase (p less than 0.01) starting during the last hour of treatment. These findings seem to confirm that endogenous opioid peptides may modulate the inhibitory effect exerted by estrogens on LH secretion, in humans.
To gain insight into the pschoneuroendocrine basis for the reduced gonadotropin secretion in the hypothalamic hypogonadotropic amenorrhea syndrome, the roles of endogenous opioids and dopamine (DA) on gonadotropin and PRL release were evaluated. Responses of LH, FSH, and PRL to a DA receptor antagonist [metoclopramide (MCP); 10 mg, iv] and to an opioid receptor antagonist (naloxone infusion; 1.6 mg/h for 4 h) were analyzed in eight patients and compared with identical studies carried out in nine normal women during the low estrogen phase of the cycle. Neither MCP administration nor the naloxone infusion induced any changes in serum gonadotropin levels in normal women. In contrast, four of eight patients responded to both receptor antagonists with a significant increase in LH levels. The LH increment elicited by naloxone exhibited an amplification of the pulsatile pattern of release, suggesting hypothalamic LRF mediation. The other four patients with prepubertal levels of basal LH and lower concentrations of PRL and estradiol failed to show LH increments in response to either receptor antagonist. There were no significant FSH changes under these experimental conditions. Mean basal PRL concentrations were lower (P < 0.01) and the acute rise in PRL levels induced by MCP were smaller (P < 0.05) in all eight patients compared to those seen in normal subjects. While the four LH responders and the four normal women exhibited no change in PRL levels during the naloxone infusion, a remarkable 100% rise in PRL was observed in the four LH nonresponders. These data suggest that at least two distinguishable forms of hypothalamic dysfunction exist in these patients; one exhibited LH increments after both opioid and DA antagonists but no PRL change in response to naloxone, and the other showed no LH increment after either receptor antagonist but did exhibit an unequivocal increase in PRL in response to naloxone. The former group may reflect an alteration of the opiate-DA system, while the latter may represent either a more severe form of the same syndrome or a distinct neuroendocrine aberration of gonadotropin and PRL secretion.
To determine the influence of ovarian sex steroid hormones on endogenous opioid regulation of pituitary FSH, LH, and PRL secretion, six women were studied during the follicular phase (days 8-9) and luteal phase (days 21-23) of their menstrual cycles. An iv bolus dose of 10 mg of the opiate antagonist naloxone was given, and plasma FSH, LH, and PRL were measured at -30, -15, 0, 15, 30, 45, 60, 90, 120, and 180 min. During the follicular phase, baseline plasma FSH and LH levels were 10.7 +/- 0.9 and 16.7 n+/- 2.0 mIU/ml (mean +/- SEM), respectively; the plasma PRL level was 11.7 +/- 1.2 ng/ml. Naloxone did not significantly alter plasma FSH, LH, or PRL during the follicular phase. Basal levels of LH were significantly lower during the luteal phase than during the follicular phase (P less than 0.01). During the luteal phase, plasma LH increased significantly from a basal level of 10.0 +/- 1.0 to 20.8 +/- 3.0 mIU at 30 min (P less than 0.001) and remained significantly elevated at 90 min. Similarly, plasma PRL increased significantly from a basal level of 11.0 +/- 0.7 to 16.2 +/- 2.7 ng/ml at 30 min (P less than 0.025), but decreased by 90 min to 12.5 +/- 1.5 ng/ml. Plasma FSH did not change after naloxone treatment. Our results suggest that endogenous opiates have a prominent inhibitory effect on pituitary gonadotropin and PRL secretion only during the luteal phase of the menstrual cycle.
I. Introduction Essentially, two modalities of luteinizing hormone (LH) secretion have been identified in the rat. The basal mode is characterized by episodic bursts of pituitary LH discharge whose frequency and amplitude may vary considerably during the day in male (1, 2) and according to different phases of the estrous cycle in female rats (4). This low level of pulsatile LH secretion is established early in the juvenile period (5). With advancing age, subtle and progressive disintegration of several compo-nents of the LH episodes seems to account for the near cessation of rhythmicity in old rats (6). Additionally, in adult female rats, the periodic mode of LH secretion is interrupted on the afternoon of proestrus by fast, high amplitude pulses constituting the preovulatory LH surge lasting for 4–6 h (7–9). The cyclic pattern of LH secretion is fully established by the 5th week of pubertal life (5). Abnormalities in periodicity, onset, duration and magnitude of the preovulatory LH discharge during middl...
1. The high percentage of fat, about 26–28% in the mature human female, may influence reproductive ability directly through two mechanisms: (a) fat converts androgens to oestrogens; (b) relative fatness influences the direction of metabolism of oestrogen to the most potent or least potent forms. The relative degree of fatness thus is directly related to both the quantity of circulating oestrogen and the biological effectiveness of the oestrogen. This is a neat mechanism for relating rates of growth, nutrition and energy outputs to the energy requirements for reproduction. Fat is the most labile body tissue; it therefore reflects environmental changes more rapidly than other tissues of the body.
2. The slow maturation of the hypothalamus and pituitary up to menarche, or first oestrus, is accompanied by a slow maturation of the body, which changes not only in size but in the relative proportion of bone, muscle, and fat. Evidence is presented that a particular threshold ratio of fat to lean mass is normally necessary for puberty and the maintenance of female reproductive ability in the human and in the rat. The synchronizing mechanisms may be metabolic, relating food intake to core temperature and/or fat storage.
3. Undernutrition and weight loss in the range of 10–15 % of normal weight for height delays menarche and causes amenorrhoea. Ballet dancers and athletes also have delayed menarche and amenorrhoea. The cessation of reproduction in both groups can be considered adaptive. Refeeding and/or cessation of intense activity results in the initiation or resumption of menstrual cycles after varying periods of time. A necessary threshold weight for height can be predicted from a fatness index.
4. Differences in the natural fertility of historical and contemporary populations may be explained by a direct effect of food intake and energy outputs on fecundity.
5. The late maturing fat - ‘sex fat’ - may have a special role in reproduction.
This study assessed the effect of the opiate antagonist naloxone on anterior pituitary hormone release in normal subjects and patients with disturbances of the gonadotropic axis. Intravenous bolus injections of naloxone resulted in a rise of plasma LH, but had no significant effect on plasma levels of FSH or PRL. It also failed to alter the LH, FSH, or TSH response to LRF and TRH, although it did augment the PRL response to TRH. Slow iv infusion of naloxone resulted in increased plasma LH and FSH concentrations in both normal subjects and patients with hyperprolactinemia. The rise of LH correlated with the mean basal LH concentrations; a low basal level only responded to naloxone with a small increase in circulating LH concentration and vice versa. This relationship of the response of LH to the resting levels also held in several other pathological states in which there were marked differences of androgen and estrogen status as well as up to a 100-fold variation in basal LH concentrations. It is concluded that LH is under inhibitory opioid control both in normal subjects and in widely differing pathological states of the gonadotropic axis.
We tested the hypothesis that suppressive effects of endogenous opiate substances are involved in certain hypogonadotropic states. For this purpose, we studied gonadotropin secretion in idiopathic hypopituitarism (five children), constitutionally delayed adolescence (five boys), and Kallmann's syndrome (three men). Endogenous opiate pathways were antagonized by the iv infusion of naloxone hydrochloride at a dose previously shown to elicit a prompt and significant increase in serum levels of LH in normal men. Under these conditions, naloxone did not increase serially sampled serum concentrations or mean urinary levels of LH: or FSH in eight patients with idiopathic hypopituitarism or Kallmann's syndrome. Gonadotropin concentrations in four of five patients with constitutional delay of adolescence also were unaffected. In one boy with clinical and biochemical indices of late pubertal development, naloxone elicited a significant increase in LH levels in blood and urine, similar to the pattern observed in normal men. In contrast to results in experimental animals, naloxone did not suppress serum PRL concentration significantly in any subject. These observations suggest that: 1) endogenous opiate mechanisms are unlikely to constitute a principal factor in maintaining hypogonadotropism in idiopathic hypopituitarism, delayed adolescence, or Kallmann's syndrome, at least acutely; 2) endogenous opiate mechanisms also cannot be implicated in the acute regulation or PRL secretion in children; and 3) the capability of adult men, but not early pubertal boys, to respond with increased gonadotropin secretion during inhibition of opiate receptors suggests that maturation of the opiate-related neuroendocrine system occurs during the course of sexual development in the human.
To determine whether endogenous opiates exert an inhibitory action on LH secretion during the menstrual cycle, LH increments were examined in response to a specific opiate antagonist, naloxone, infused at 1.6 mg/hr for 4 hrs. Naloxone had no discernible effect on LH release during the early follicular phase. By contrast, a significant LH increment was observed in both the late follicular and mid-luteal phases of the cycle but the patterns of LH increment were distinct. Late follicular subjects exhibited slow, progressive increases in LH, while prompt, episodic and quantitatively greater LH increments were evident in mid-luteal phase subjects. These observations suggest that endogenous opiates are involved in the regulation of LH secretion during the high estrogen and estrogen-progesterone phases of the menstrual cycle.
To evaluate whether the efficacy of naltrexone administration in patients with hypothalamic amenorrhea correlates to the response to an acute naloxone test.
Thirty patients with hypothalamic amenorrhea associated with weight loss were studied. After naloxone test (4 mg in bolus IV) patients were divided into two groups: group A, nonresponsive (n = 15) and group B, responsive (n = 15). Group A underwent two cycles of hormonal replacement therapy with E2 patches and medroxyprogesterone acetate. Then all patients were administered naltrexone at the dosage 50 mg/d orally for 6 months. A third group of 10 amenorrheic patients were treated with oral placebo with the same schedule.
Plasma gonadal steroid levels increased in all patients and in 24 of 30 patients the menstrual bleeding occurred within 90 days from the beginning of treatment. After 6 months from naltrexone discontinuation, 18 of 24 patients still showed the occurrence of menstrual cycles. Luteinizing hormone plasma levels and LH pulse amplitude increased after 3 months of treatment and remained unchanged 6 months after naltrexone suspension. Plasma FSH levels did not show any change in any patient. The body mass index increased after 3 months in all patients who menstruated. Patients treated with placebo did not show any significant change in gonadotropins and gonadal steroid plasma levels.
The present study supports the efficacy of naltrexone therapy for patients with hypothalamic amenorrhea either responsive or nonresponsive to naloxone test.
The possible differential regulation of pulsatile follicle stimulating hormone (FSH) and luteinizing hormone (LH) secretion in pre-pubertal children and in post-menopausal women was investigated. Children were studied for 4 h and post-menopausal women for 6 h; blood samples were taken every 10 min. Post-menopausal women were studied before and 21 days after administration of a single i.m. dose of gonadotrophin-releasing hormone (GnRH) analogue. Eight post-menopausal women and 18 children (nine boys and nine girls) were enrolled. The children were divided into two groups: A, at Tanner stages 0-1 (four boys and three girls); B, at Tanner stage 2-3 (five boys and six girls). Plasma LH and FSH concentrations were determined using an immunofluorimetric assay. Time series were analysed and the specific concordance (SC) index was computed to determine the degree of concordance between episodes of LH and FSH secretion. While children of group A had LH concentrations below the minimal detectable dose of 0.1 IU/l, group B showed measurable LH plasma concentrations (1.4 +/- 0.3 IU/l, mean +/- SEM). Plasma FSH concentrations were detectable in both groups. Group A showed FSH plasma concentrations significantly lower than those of group B (0.75 +/- 0.2 and 1.95 +/- 0.4 IU/l respectively; P < 0.05), but FSH pulse frequency was higher in group A (P < 0.05). Children of group B showed significant concomitance of LH and FSH secretory events at time 0 (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Amenorrhea associated with weight loss is characterized by several neuroendocrine aberrations. The aim of the present study was to define the characteristics of episodic secretion of prolactin in women with weight loss-related amenorrhea. To evaluate whether hypoestrogenism was responsible for the changes in prolactin secretion in amenorrheic women, the pulsatile secretory pattern was also studied during hormone replacement therapy (HRT). Fifteen patients were studied by blood sampling every 10 min for 8 h. Four normally cycling women were studied as a reference group, during both the midfollicular and midluteal phases. Mean plasma prolactin levels and pulse amplitude were lower in amenorrheic patients than in controls. The prolactin pulse frequency was higher than that in controls during the follicular phase, but lower than controls during the luteal phase of the menstrual cycle. During HRT, mean plasma prolactin levels significantly increased, pulse frequency decreased and pulse amplitude significantly increased both during estradiol and estradiol plus medroxyprogesterone acetate administration. In conclusion, in amenorrhea associated with weight loss the chronobiological organization of prolactin secretion is deranged, both as a result of a neuroendocrine alteration and as a result of low plasma levels of gonadal steroids.
Corticotropin-releasing factor (CRF) plays a role in coordinating endocrine, autonomic and behavioral responses to stressful stimuli. Benzodiazepines exert many effects which are antithetical to those of CRF, including anxiolysis and suppression of the pituitary-adrenal axis. Although there is evidence that benzodiazepines can modulate several electrophysiological and behavioral responses to exogenous CRF, we questioned whether this class of drug might also affect CRF biosynthesis as well. We have shown previously that footshock stress increases CRF mRNA levels as monitored by in situ hybridization histochemical techniques in the paraventricular nucleus (PVN) and Barrington's nucleus (the pontine micturition center). We report here the effects of the potent benzodiazepine, chlordiazepoxide (CDP), on stress-induced CRF mRNA accumulation in these two regions. Male albino rats were exposed to electrical footshock (1.5 mA, 1-s duration, 60 times/30 min) twice daily for 4 days and sacrificed 24 h after the last shock session. Either CDP (1, 2.5, 5 or 10 mg/kg) or saline was given i.p. 30 min before each stress. Sections were hybridized with an 35S-labeled prepro-CRF cRNA probe. Relative levels of CRF mRNA were quantified by densitometry of the autoradiography with X-ray film. CRF mRNA concentrations were significantly increased in both the PVN and Barrington's nucleus after stress, and CDP attenuated these increases in the PVN. By contrast, CDP did not affect CRF mRNA accumulation in Barrington's nucleus after stress. The results suggest that the benzodiazepine, CDP, suppresses stress-induced pituitary adrenal activation at least in part through inhibition of CRF production in the PVN.(ABSTRACT TRUNCATED AT 250 WORDS)
States of chronic undernutrition can cause a profound suppression of reproductive function. To begin to determine the time course and the nature of the mechanism by which undernutrition suppresses the activity of the reproductive axis we have examined the effects of brief periods of fasting on reproductive hormone secretion in men and male rhesus monkeys. In monkeys there is a significant suppression of pulsatile luteinizing hormone (LH) and testosterone secretion after a single day of fasting, that is apparent within the first 4 h after a meal is missed. The suppression of pulsatile LH secretion on a day of fasting does not appear to be caused by the psychological stress experienced when monkeys are deprived of their daily meal in that monkeys who are maintained in a metabolically fed state (by feeding a large excess of food on the day prior to fasting), but are deprived of a meal and displayed behavioural agitation associated with fasting, have no suppression of LH secretion. The suppression of LH secretion on a day of fasting cannot be reversed by naloxone infusion, indicating that increased secretion of opioid peptides is not the primary mechanism causing the decrease in the central drive to the reproductive axis during fasting.(ABSTRACT TRUNCATED AT 250 WORDS)
To define the characteristics of spontaneous GH episodic secretion and the modulatory role of gonadal steroids in patients with hypothalamic amenorrhea associated with weight loss.
Women were studied for 8 hours, sampling every 10 minutes, and plasma GH levels were measured by RIA.
Fifteen patients with weight-loss-related amenorrhea were studied in baseline conditions. Five out of 15 patients underwent two cycles of hormonal replacement therapy with E2 patches (100 micrograms every 3 days for 24 days) and medroxyprogesterone acetate (MPA) (10 mg/d, from day 12 to day 24). On the second cycle of therapy, the pulsatility study was repeated twice: after only estrogen (day 11) and after E2 plus progestin (day 22). Four normally cycling women were studied as a reference group during midfollicular and midluteal phases.
Amenorrheic patients showed mean plasma GH levels similar to healthy women during the follicular phase but significantly lower than those observed during the luteal phase. GH pulse frequency was higher in patients than in controls, whereas pulse amplitude was comparable with the follicular phase but lower during the luteal phase. During the hormonal replacement therapy, when only E2 was administered, GH pulse frequency decreased, whereas GH integrated plasma concentrations and GH pulse amplitude increased significantly. After MPA and E2 administration, GH pulse amplitude and GH plasma levels decreased, which was similar to pretreatment condition.
The present study demonstrated that in amenorrhea associated with weight loss the frequency of GH episodic release is significantly higher than in normally cycling women. Moreover, a different modulatory role of estrogen (increased amplitude) and P (decreased amplitude) on the episodic release of GH in amenorrheic women undergoing a replacement treatment was shown by the present data.