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Biomedical subjects

A D Genazzani

Publications and source records attributed to A D Genazzani.

At least 91 records · Page 5Linked to original sources

FSH secretory pattern and degree of concordance with LH in amenorrheic, fertile, and postmenopausal women.

Pulsatile secretion of gonadotropin was investigated in amenorrheic patients and in fertile and postmenopausal women to assess both follicle-stimulating hormone (FSH) episodic secretion and its temporal coupling with luteinizing hormone (LH). Three groups of amenorrheic patients were studied: hyperandrogenic (n = 20), hypogonadotropic (n = 51), and normogonadotropic (n = 31). Nineteen fertile women (during the follicular and luteal phases of the cycle) and sixteen postmenopausal women were investigated as reference groups. All subjects demonstrated the presence of a distinct pulsatile pattern with LH and FSH pulses/4 h as follows: hyperandrogenic 3.95 +/- 0.26 and 3.85 +/- 0.2, hypogonadotropic 3.76 +/- 0.26 and 3.9 +/- 0.16, normogonadotropic 3.5 +/- 0.2 and 3.9 +/- 0.17 LH and FSH pulses/4 h, respectively (means +/- SE). Normal controls showed 4.1 +/- 0.2 and 3.1 +/- 0.2 pulses/4 h for LH (P < 0.05) and 3.2 +/- 0.1 and 3.6 +/- 0.3 pulses/4 h for FSH, during follicular and luteal phases, respectively. Postmenopausal women showed 3.6 +/- 0.2 and 3.0 +/- 0.3 pulses/4 h for LH and FSH, respectively. Specific concordance (SC) index demonstrated that LH and FSH were significantly and simultaneously secreted in all groups. Conversely, LH and FSH were not temporally related during the luteal phase. In conclusion, we report a distinct FSH episodic secretion and its temporal linkage with LH pulses irrespective of plasma concentrations of gonadal steroids in secondary amenorrhea.

Activity Cycles↗

Effect of different chronic intermittent stressors and acetyl-l-carnitine on hypothalamic beta-endorphin and GnRH and on plasma testosterone levels in male rats.

Chronic stress affects the reproductive function by modifying the neuroendocrine homeostasis. The aim of the present study was to clarify the neuroendocrine and the gonadal changes following chronic intermittent stress in male rats and the action of a neuroactive drug, acetyl-l-carnitine (ALC). The effect of two different stressors, cold water swimming or ether, on central beta-endorphin (beta-EP) and GnRH contents, and on plasma testosterone levels was investigated. In addition, the response to an acute stress in chronically stressed rats, treated or untreated with ALC (10 mg/day/rat p.o.), was evaluated. The stressors were applied twice a day for 10 days, and rats were killed before, during and after the last stress session. Mediobasal hypothalamus (MBH) beta-EP and GnRH contents, and plasma testosterone levels were evaluated by radioimmunoassay. The following results were obtained: (1) both chronic swimming and ether stress caused a decrease in hypothalamic beta-EP contents; (2) MBH GnRH contents increased after chronic swimming stress but not after ether stress; (3) chronic swimming stress induced a twofold decrease in plasma testosterone levels, while no changes were observed after ether stress; (4) the treatment with ALC prevented the decrease in plasma testosterone levels after chronic swimming stress, and (5) acute stress in chronically stressed animals caused an increase in MBH-beta-EP. The present data showed that chronic swimming stress reduces the reproductive capacity and impairs the capacity to respond to the acute stress and that ALC modulates the hormonal changes to physical stress and prevents the antireproductive effect of chronic cold swimming.

Acetylcarnitine↗

Neuroendocrine changes in luteal function in patients with premenstrual syndrome.

The present study evaluates the luteal progesterone (P) and LH secretions in 14 patients affected by premenstrual syndrome (PMS) and in 14 asymptomatic controls through the evaluation of their episodic release. PMS was prospectively confirmed in two consecutive menstrual cycles using Moos' Menstrual Distress Questionnaire. A pulsatility study was performed during the luteal phase. Blood samples were drawn every 10 min for 12 h, beginning at 0800 h. Statistically significant pulses were detected using the Detect program, and the degree of concordance of LH and P pulses was estimated. Similar mean 12-h P levels were found in controls (mean +/- SD, 13.9 +/- 9.3 nmol/L) and patients (14.2 +/- 10.1). LH levels were also similar in the two groups. Patients showed a higher P pulse frequency (13.4 +/- 1.8 vs. 11.4 +/- 2.3; P < 0.02) and a reduced amplitude of secretory episodes (126.5 +/- 61.6% vs. 187.1 +/- 126.7%; P < 0.03) than controls. Similarly, PMS patients showed pulsatile LH release of increased frequency and reduced amplitude than controls. A significant degree of concordance between LH and P pulses was observed in both groups, with a time lag of 0-10 min; that is, P secretory episodes follow LH with a delay of 0-10 min. These findings demonstrate that despite the fact that integrated P levels in PMS patients are similar to those in control subjects, the episodic secretion of the hormone is characterized by pulses of increased frequency and reduced amplitude. This phenomenon is temporally related to LH secretion, thus reinforcing the concept of PMS as a neuroendocrine disorder.

Adult↗

The concomitant release of androstenedione with cortisol and luteinizing hormone pulsatile releases distinguishes adrenal from ovarian hyperandrogenism.

Androstenedione secretory characteristics and its possible temporal correlation with luteinizing hormone (LH) and/or cortisol, intended as the markers of, respectively, ovarian stimulation and adrenal secretion, were evaluated in 24 patients affected by clinical hyperandrogenism. A pulsatility test was carried out for 8 h, with sampling every 10 min, and LH, cortisol and androstenedione profiles were determined by radioimmunoassay. Time series were analyzed with the computer program DETECT and with a program for specific concordance estimation. A distinct episodic release of LH, cortisol and androstenedione was observed in all patients (6.9 +/- 0.8, 5.2 +/- 0.6 and 5.5 +/- 1 peaks/8 h, respectively). When specific concordance was tested between LH and androstenedione, and between cortisol and androstenedione, two distinct groups of patients could be identified. Group A (n = 13) showed a significant specific concordance (SC) index only for LH and androstenedione while group B (n = 11) showed a significant SC also for cortisol and androstenedione, thus demonstrating a consistent adrenal participation in the androstenedione secretion in these patients. In addition, specific differences were observed on androstenedione secretory profiles of group B which showed a significant (p < 0.05) decrease of androstenedione plasma concentrations emulating cortisol behavior. No such observation was noted in group A, whose androstenedione plasma levels did not show any reduction. In conclusion, our data support the use of circulating androstenedione, LH and cortisol plasma levels and copulsatile assessment to distinguish the presence of two populations of hyperandrogenic patients: one whose hyperandrostenedionemia is mainly due to ovarian secretion (group A) and one which showed a hyperactivation of the adrenal gland (group B).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗

Hypothalamic amenorrhea: evidence for a central derangement of hypothalamic-pituitary-adrenal cortex axis activity.

OBJECTIVE: To evaluate the activity of the hypothalamic-pituitary-adrenal axis (HPA) in patients with hypothalamic amenorrhea. PATIENTS, PARTICIPANTS: Amenorrheic women with a history of emotional stressful events and eumenorrheic women as control group were studied. DESIGN: Pulsatile cortisol (F) secretion over a 4-hour period of time and plasma F responses to various neuroendocrine tests (naloxone, fenfluramine, corticotropin-releasing hormone [CRH], adrenocorticotropic hormone) were investigated. RESULTS: Women with hypothalamic amenorrhea showed a F secretory pattern higher than normal women. In addition, the lack of naloxone or fenfluramine-induced release of F and a blunted F response to CRH test were observed. CONCLUSION: The increased activity of HPA in patients with hypothalamic amenorrhea is associated with an impaired activity of some central pathways (opioids and serotonin), suggesting multiple alterations in the hypothalamic control of pituitary-adrenal axis in amenorrheic women.

Adolescent↗

The brain as a target organ of gonadal steroids.

Gonadal steroids have many effects in the central nervous system. Through a feedback mechanism, they influence the synthesis and release of hypothalamic gonadotropin-releasing hormone (GnRH) and/or pituitary gonadotropic hormones (luteinizing hormone, LH, and follicle stimulating hormone, FSH). Endogenous opioid peptides (EOPs) represent one of the key factors modulating the activity of sex steroids on the hypothalamus-pituitary-gonadal (HPG) axis. In particular, these peptides control the secretion of LH by inhibiting the activity of the hypothalamic neurons which produce GnRH. The EOP effect is dependent on the steroid hormone milieu, as shown by different responses to naloxone administration, both in animals and in humans. For the naloxone-induced increase in LH secretion to occur, relatively high levels of sex steroids are required. In humans, LH release is absent before sexual maturation. In fertile women, naloxone administration increases LH levels in the luteal phase but not in the follicular phase. In the postmenopausal period, naloxone has no effect on LH release; estrogen/progestin therapy does restore the LH response.

Aging↗

Pulsatile secretion of gonadotropins and prolactin during the follicular and luteal phases of the menstrual cycle: analysis of instantaneous secretion rate and secretory concomitance.

OBJECTIVE: To characterize the pulsatile secretions of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (PRL) during the menstrual cycle and to statistically evaluate their secretory concomitance. DESIGN: Pulsatility study performed during the midfollicular and midluteal phases of a same menstrual cycle, blood samples being collected every 10 minutes for 6 hours. SETTING: Participants investigated in the Division of Endocrinology, University Hospital. PARTICIPANTS: Nine healthy women (22 to 38 years) with regular menstrual cycles. MAIN OUTCOME MEASURES: Plasma LH, FSH, and PRL values were analyzed as raw and deconvoluted data, and the specific (nonrandom) secretory concomitance was evaluated statistically. RESULTS: The pulsatile secretion of LH was confirmed, and that of FSH and PRL was clearly established during both phases of the cycle by characterization of peak frequency, period, and amplitude. A specific secretory concomitance was assessed between LH and FSH in the follicular but not the luteal phase, and a tight concomitance between LH and PRL was demonstrated during both phases. CONCLUSIONS: These results are supportive of significant pulsatile secretions of the three hormones during the menstrual cycle, and they are demonstrative of a definite copulsatility of these hormones, suggestive of common regulatory factors in the complex temporal patterns of gonadotropin and PRL secretions along the cycle.

Adult↗

Frequency of prolactin pulsatile release in normal men and in agonadal patients is neither coupled to LH release nor influenced by androgen modulation.

OBJECTIVE: We wished to examine and characterize the prolactin pulsatile secretory pattern in both normal and agonadal males in order to assess whether there was any concordance with LH secretion. DESIGN: Patients were sampled every 5 minutes for 12 hours. PATIENTS: We studied five normal and four agonadal men, the latter group before and on testosterone enanthate (TE) (200 mg i.m. every 15 days) treatment. MEASUREMENTS: Prolactin and luteinizing hormone plasma levels were determined using commercial RIA systems. Pulse detection was performed using the DETECT program and the degree of concordance between luteinizing hormone and prolactin was established computing the specific concordance index. RESULTS: We demonstrated the presence of a frequent PRL secretory pattern in normal men (22.8 +/- 1.8 peaks/12h; mean +/- SEM) and in agonadal patients, both in basal conditions and during testosterone treatment (20.5 +/- 2.8 and 18 +/- 1.6 peaks/12h, respectively). The testosterone treatment in agonadal men significantly reduced luteinizing hormone pulse frequency (baseline: 27.5 +/- 2, testosterone administration: 18 +/- 1.3 peaks/12h, P < 0.01) but did not affect pulsatile prolactin release. Using a 10 and 15 minute sampling protocol, we observed that prolactin pulse frequency significantly decreased (P < 0.01) and was similar to the frequencies estimated in previous reports. When luteinizing hormone and prolactin time series were studied to evaluate the possible presence of a specific concordance (SC) between the secretory events of the two hormones, no significant degree of concomitancy was observed neither using the specific concordance index or the cross-correlation analysis. CONCLUSIONS: This report demonstrates (a) the presence of frequent pulsatile release of prolactin in both controls and agonadal patients (baseline and on testosterone enanthate), (b) the use of an appropriate sampling interval (5 minutes) to unmask the prolactin pulsatile release, (c) that in men, luteinizing hormone secretory events are not temporally linked to prolactin secretion, and (d) that androgens, even if reducing luteinizing hormone pulse frequency in agonadal patients, do not significantly affect prolactin pulsatile secretion, suggesting that testosterone and its metabolites do not affect lactotroph activity.

Adult↗

Melatonin treatment delays reproductive aging of female rat via the opiatergic system.

In female rat age-related reproductive decline is accompanied by progressive impairment of the neuroendocrine mechanisms that regulate LH secretion. The biosynthetic activity of the pineal gland is markedly depressed and the nocturnal secretion of melatonin decreases significantly. The aim of the present study was to evaluate whether the nocturnal administration of melatonin via the drinking water (0.4 micrograms/ml) throughout the course of aging from 14 to 24 months of age could (1) influence the age-related changes that occur in basal serum levels of LH and in the LH response to GnRH or to naloxone stimulation at 16, 18 and 20 months of age, and (2) delay the onset of the postreproductive constant estrous-anovulatory state as evaluated by the daily recording of vaginal smears and by occurrence of polyfollicular ovaries at 24 months of age. Our results demonstrate that melatonin replacement delays the increase in LH serum levels and the decrease in LH response to GnRH that occur in 18-month-old control animals. Furthermore, they show that melatonin treatment prevents the loss of LH response to naloxone manifested in control rats between 16 and 20 months of age. Melatonin also appears to prevent the progressive increase in the monthly occurrence of estrus phases as well as to decrease the number of rats with polyfollicular ovaries at 24 months of age in comparison to control animals. These results suggest that the age-related decrease in circulating melatonin during the night may contribute to the reproductive decline of aging, and that this effect may involve the central opioid system.

Aging↗

Inhibin and activin modulate human monocyte chemotaxis and human lymphocyte interferon-gamma production.

Inhibin and activin are referred to as gonadal glycoprotein hormones whose function is the control of FSH release from the pituitary gland. However, several observations indicate that inhibin and activin are produced in various organs and serve multiple functions. Because bone marrow and spleen produce inhibin and activin, our aim was to evaluate their possible effect on cell-mediated immune function. For this reason we studied 1) monocyte chemotaxis, 2) lymphocyte interferon-gamma production, 3) phytohemagglutinin-induced lymphocyte proliferation, and 4) nonmajor histocompatibility complex-restricted and lymphokine-activated lymphocyte cytotoxicity. All studies were performed on human peripheral blood cells in the absence or presence of various doses of inhibin, activin, or inhibin plus activin. A significant dose-related increase in monocyte chemotaxis was induced by inhibin. Activin increased the migrational activity of monocytes, but via random, not directed, migration. Inhibin significantly decreased interferon-gamma production, and its effect was reversed by activin. Inhibin and/or activin had no significant effect on either phytohemagglutinin-induced lymphocyte proliferation or lymphocyte cytotoxic capability. The present demonstration that inhibin and activin may affect some immune parameters suggests a possible involvement of these hormones in regulating cell-mediated immune function.

Activins↗

Luteinizing hormone (LH) secretory burst duration is independent from LH, prolactin, or gonadal steroid plasma levels in amenorrheic women.

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.

Adolescent↗

Objective assessment of concordance of secretory events in two endocrine time series.

A new objective method is presented for investigating the presence of a temporal relationship between episodic release of two hormones. The two time series of hormone concentrations are first analysed by an objective method for peak detection. Both data series are then transformed into "quantized" or discretized series by recording the occurrence of a hormone pulse as an "event", characterized by the onset, the maximum, or another unique feature. The two quantized series are then matched, and the number of concordant events and discordant events are counted. Each point in series A is compared with a "time-window" of a selected number of points in series B, to accommodate small degree of mismatch between events in the two series. An index of concordance is computed, compensating for any spurious random coincidence: the "Specific Concordance", to evaluate the frequency of concordant events in excess of those expected on the basis of chance alone. This calculation is systematically repeated, interposing a range of time-lags between the two series. A graph of Specific Concordance versus time-lag indicates the time-lag corresponding to a maximal concordance. Simulations of random series of events are performed, and their degree of concordance is evaluated in a similar fashion, thus generating frequency distributions of Specific Concordance values under the null hypothesis of no temporal relationship. This permits the selection of criteria for statistical significance at any desired p-level, for one or many lag times, and for one or multiple subjects. Various degrees of concurdance can also be stimulated to evaluate the performance (sensitivity, statistical power) of this approach. These methods have been implemented as a collection of short microcomputer programmes, and applied to the study of the temporal relationship between beta-endorphin and cortisol in normal subjects sampled every 10 min for 24 h. This analysis demonstrated concordance between events in the two series, with synchronous occurrence of beta-endorphin and cortisol release events significantly more frequently than expected on the basis of random association (p less than 0.01).

Adult↗

Use of the receiver operating characteristic curve to evaluate sensitivity, specificity, and accuracy of methods for detection of peaks in hormone time series.

We utilize the "Receiver Operating Characteristic" to describe the relationship between sensitivity and specificity as the threshold for peak detection is varied systematically, to provide objective comparison of the performance of methods for detection of episodic hormonal secretion. A computer program was used to generate synthetic data with peaks with variable durations, with constant or variable height, shape and/or interpulse interval. This approach was used to compare the CLUSTER and DETECT programs. For both programs, the observed false positive rates estimated using signal-free data were in good agreement with the nominal rates, but in the presence of signal the observed false positive rates were systematically lower. Sensitivity increases with increasing signal/noise ratio, as expected. Program DETECT, using its standard options, provided excellent sensitivity (90-100%) with very low false positive rate under all conditions tested. Its performance could be further improved by the use of a more stringent definition of a peak requiring the presence of "UP" followed by a "DOWN". The CLUSTER program was found to have very poor sensitivity when using the "local variance" option. Use of the true fixed standard deviation or percent coefficient of variation resulted in a modest improvement. Optimal performance of program CLUSTER was obtained by the use of the best of 3 variance models, testing 12 different cluster sizes (from 1x1 to 4x4) and selecting the best among these: under these conditions it can achieve high sensitivity (90-100%) for very low observed false positive rate, such that its performance was comparable to that of DETECT. The methods developed and illustrated here should permit the definitive characterization and validation of the performance of any one method, the objective comparison of the relative performance of two or more methods for analysis of pulsatile hormone levels for episodic hormone secretion, and lead to the improvement of algorithms for peak detection.

Hormones↗

The effect of various drugs with neuroendocrine activity and transdermal estradiol on plasma gonadotropin concentrations after ovariectomy in reproductive-aged women.

In the present study we compared the effect of different neuroactive drugs with that of estrogen treatment on the ovariectomy-induced plasma luteinizing hormone (LH) and follicle-stimulating hormone (FSH) changes. A total of 35 menstruating women undergoing ovariectomy were randomly divided into five groups of 7 patients each, receiving a 4-week treatment with oral clonidine, lisuride and sodium valproate, transdermal 17 beta-estradiol, or placebo. The treatment started the day after ovariectomy. Surgery was done during the early follicular phase of the cycle. Blood samples were collected before and after 3, 5, 7, 14, 21 and 28 days of treatment. During the treatment, hot flushes were subjectively recorded. The placebo-treated group showed a progressive increase in plasma LH and FSH concentration during the month following ovariectomy. The same changes occurred in the lisuride and sodium valproate treated groups. Plasma LH levels in ovariectomized women treated with clonidine showed an increase which was higher than in placebo-treated women (p less than 0.01), while FSH levels were similar to those in the placebo group. In the estradiol-treated group the increase in both gonadotropins was significantly less (p less than 0.01) than in the placebo group. The frequency and intensity of hot flushes were high in placebo and sodium valproate treated subjects, being significantly reduced by clonidine, lisuride and estrogen treatment. Our results seem to indicate that clonidine treatment modulates the LH postcastration rise and that both neuroendocrine and gonadal mechanisms influence the changes in the activity of the GnRH-pituitary axis following ovariectomy.

Administration, Cutaneous↗

Acetyl-l-carnitine as possible drug in the treatment of hypothalamic amenorrhea.

Several neuroendocrine disregulations have been demonstrated in patients with hypothalamic amenorrhea, but a definite therapeutic strategy has not yet been found. Since acetyl-l-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 less than 3 mIU/ml, and B) normogonadotropic: 10 subjects with plasma LH greater than 3 mIU/ml. All subjects underwent: 1) a pulsatility study (4 h sampling every 10 min), 2) GnRH test (two bolus injections of 10 micrograms at time 0 and +120), 3) TRH test (200 micrograms). 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 less than 0.05) (mean +/- SEM), a significant increase in LH pulse amplitude (p less than 0.01) with no changes in LH pulse frequency, and a significantly increased response of LH to the latter GnRH bolus during the GnRH test. Hypogonadotropic patients also showed a significant increase in both estradiol (from 18.8 +/- 2.5 to 48 +/- 3.3 pg/ml, p less than 0.05) and PRL (from 6 +/- 1 to 11.4 +/- 1.7 ng/ml, p less than 0.05). No significant differences were observed in the hormonal parameters of normogonadotropic patients after 6 months of ALC therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcarnitine↗

Specific concordance index defines the physiological lag between LH and progesterone in women during the midluteal phase of the menstrual cycle.

Using a recently developed statistically based method for assessment of the degree of concordance, we evaluated the degree of specific concordance (SC) between luteinizing hormone (LH) and progesterone secretory patterns. Eight healthy women volunteered for this study, undergoing a 12-h pulsatility study, sampling every 10 min. LH and progesterone pulse frequencies were estimated with the program DETECT (9.75 +/- 1 and 11.5 +/- 0.9 pulses/12 h, respectively; mean +/- SEM). The temporal relationship between LH and progesterone secretions was evaluated with cross-correlation analysis and with the computation of the SC index. Cross-correlation showed concordance between LH and progesterone (p less than 0.05) at a range of lag between 0 and 40 min, while the SC index indicated that LH and progesterone pulses were significantly (p less than 0.05) and maximally correlated at 10-min lag. In conclusion, our data demonstrated that the specific concordance confirms the statistically significant concordance of LH and progesterone secretory events in women during the midluteal phase. In addition, the use of this new, objective, statistically based approach permits, compared to traditional cross-correlation analysis, a more precise definition of the physiological time lag for temporal coupling of secretory events between the two hormones.

Adult↗