Follicular phase hypothalamic-pituitary-gonadal axis function in women with fibromyalgia and chronic fatigue syndrome

OBJECTIVE: Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are clinically overlapping stress associated disorders. Neuroendocrine perturbations have been noted in both syndromes, and they are more common in women, suggesting abnormalities of gonadal steroid hormones. We tested the hypothesis that women with FM and CFS manifest abnormalities of the hypothalamic-pituitary-gonadal (HPG) hormonal axis. METHODS: We examined the secretory characteristics of estradiol, progesterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH), including a detailed analysis of LH in premenopausal women with FM (n = 9) or CFS (n = 8) during the follicular phase of the menstrual cycle compared to matched healthy controls. Blood was collected from an indwelling intravenous catheter every 10 min. over a 12 h period. LH was assayed from every sample; pulses of LH were identified by a pulse-detection program. FSH and progesterone were assayed from a pool of hourly samples for the 12 h period and estradiol from samples pooled over four 3 h time periods. RESULTS: There were no significant differences in FSH, progesterone, or estradiol levels in patients versus controls. There were no significant differences in pulsatile secretion of LH. CONCLUSION: There is no indication of abnormal gonadotropin secretion or gonadal steroid levels in this small, but systematic, study of HPG axis function in patients with FM and CFS.     

Assessment of pituitary gonadotropin release to gonadotropin releasing hormone/thyroid-stimulating hormone stimulation in women with systemic sclerosis

OBJECTIVE: To evaluate basal and dynamic levels of pituitary gonadotropin release in female systemic sclerosis (SSc) patients of childbearing age and in post-menopausal SSc patients. METHODS: We performed stimulation tests for gonadotropin-releasing hormone (GnRH) and thyroid-stimulating hormone (TRH) during the early follicular phase in 12 women of childbearing age [mean age (S.E.M.) 34.8 (2.4) yr] with SSc to determine serum concentrations of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin. Blood samples were also obtained from six post-menopausal women with SSc [mean age 46.8 (2.4) yr], after TRH stimulation; only serum prolactin concentration was determined, because elevated basal concentrations of FSH and LH were expected. Hormone concentrations were estimated by radioimmunoassay. Comparisons were made with healthy control women matched for age and reproductive status. RESULTS: In SSc patients of childbearing age, basal FSH, LH and oestradiol (E(2)) levels were not significantly different from those in controls, whereas basal prolactin concentration was significantly higher than in controls (P=0.0001). After the stimulation test, the peak concentrations of FSH (P=0.0001) and prolactin (P<0.0001) were significantly higher than in controls. The net integrated response curves [net area under the curve (AUC)] for FSH and LH did not differ significantly between SSc patients and controls. On the contrary, the net AUC for prolactin in response to TRH stimulation was significantly higher than in controls (P=0.001). In post-menopausal patients, basal E(2), FSH, LH and prolactin levels were not significantly different between women with SSc and controls. However, after TRH stimulation, peak levels and net AUC for prolactin were not significantly higher in patients than those in controls. No significant correlations were found between basal and stimulated FSH, LH and prolactin levels and the severity of involvement of various organ systems. Multiple regression analysis showed that basal and stimulated prolactin concentrations were associated with skin sclerosis and peripheral vascular and lung involvement. CONCLUSION: Our results suggest that subclinical primary hypogonadism can occur in SSc patients. They also confirm an alteration in the mechanism for prolactin secretion and release, which may not only contribute to further disturbance of the reproductive axis but may also have an influence on the disease.     

HORMONE PROFILE IN PREMENSTRUAL TENSION: EFFECTS OF BROMOCRIPTINE AND DIURETICS

Plasma levels of prolactin, FSH, LH, progesterone and 17-beta-oestradiol in twenty women with premenstrual tension were compared with those in twenty controls. The former group was studied also during treatment with bromocriptine. The mean prolactin level in the PMT group was lower in the follicular phase than in the luteal phase (P less than 0.01), but there was no difference between the PMT and control group in the luteal phase. No differences were found between the controls and the PMT group in FSH,LH, 17-beta-oestradiol and progesterone levels in the luteal phase. Bromocriptine suppressed prolactin concentrations (P less than 0.01), but had no effect on the FSH, LH, 17-B-oestradiol or progesterone levels.     

PROLACTIN LEVELS DURING THE MENSTRUAL CYCLE*

The levels of prolactin, FSH, LH, oestradiol and progesterone were measured daily during fourteen ovulatory cycles. The behaviour of FSH, LH, oestradiol and progesterone was classical. Non-systematic changes occurred in prolactin levels during the course of the menstrual cycle with the highest level being either during the ovulatory period or during the luteal phase. However, the mean level of prolactin was significantly higher during the ovulatory and luteal phases than during the follicular phase. A direct relationship between oestradiol and prolactin levels was noted, although there was no correlation between prolactin on the one hand and FSH, LH and progesterone on the other.     

Relationship between the endocrine environment within the Graafian follicle and the subsequent rate of progesterone secretion by human granulosa cells in vitro.

The steroidogenic potential of granulosa cells harvested from human Graafian follicles containing varying concentrations of pituitary and steroid hormones was examined. The mitotic activity and production of progesterone by granulosa cells in vitro was found to be correlated with their hormonal environment at the time of harvesting. Only cells from follicles containing some FSH and high concentrations of oestradiol underwent spontaneous mitosis in vitro. However, mitosis could be induced by adding FSH and high concentrations of oestradiol to the culture, provided that the concentration of LH was low. Cells harvested from follicles containing LH, FSH and high concentrations of oestradiol secreted significantly more progesterone than cells from follicles which did not contain all three hormones. It is suggested that after the initiation of follicular development by FSH, a long period of exposure (8-10 Days) to both FSH and oestradiol is necessary before the maximum biosynthetic capacity of granulosa cells is achieved; this synthetic potential is then only realized under the influence of LH and prolactin. Premature exposure to LH inhibits both the mitotic activity and the steroidogenic potential of these cells.     

Oestrogens and prolactin as possible regulators of puberty.

At day 15 after birth, high serum oestradiol levels, high FSH levels and occasionally high LH levels were observed in control female rats. Injections of potent and specific antisera for oestrogen between days 8-15 prevented LH peaks and decreased basal LH levels. Serum FSH levels were increased after treatment. High oestradiol levels at this time appear to exert a positive feedback action on phasic as well as tonic LH release. Injections of ovine prolactin (0.5 mug/g body wt twice daily) between days 8-25 of life significantly advanced the day of vaginal opening in immature rats and initiated regular oestrous cycles. Such treatment completely prevented high LH levels at day 15 but serum FSH levels remained high. Prolactin and progesterone levels were higher at day 25 than at day 15 in control rats and at that time LH and FSH levels were low. Prolactin treatment had a depressant effect on endogenous prolactin and progesterone levels. It is proposed that after day 20 the positive feedback threshold of oestradiol on LH release is at a mature, highly sensitive level. The steady increment in serum prolactin and/or progesterone levels between day 20 and puberty, however, inhibited phasic LH release thus preventing early puberty. The possible mechanisms of action of prolactin are discussed.     

CHANGES IN PLASMA LEVELS OF PROLACTIN, IN RELATION TO THOSE OF FSH, OESTRADIOL, ANDROSTENEDIONE AND PROGESTERONE AROUND THE PREOVULATORY SURGE OF LH IN WOMEN

Plasma samples were obtained at 8 hourly intervals around the preovulatory surge of LH in three groups of women with spontaneously ovulatory menstrual cycles, in order to clarify the hormonal events around the time of ovulation. In 21 of 25 women in whom samples were collected every 8 hours the start of the LH surge occurred between midnight and 0800. In 16 of these women the concentration of LH, FSH and progesterone was measured every 8 hours around the pre-ovulatory surge of LH. A progressive increase in progesterone started with the onset of the LH surge, with a transient fall after 32-40 h at a time coincident with that of ovulation. In 10 women oestradiol, androstenedione and prolactin were measured 8 hourly around the pre-ovulatory surge of LH beginning at 0800 h. Prolactin showed a sustained increase in levels beginning at the start of and lasting for the duration of the pre-ovulatory LH surge; oestradiol levels did not rise around this time, and declined by 24 h after the onset of the LH surge. These results suggest that (1) the pre-ovulatory LH surge begins between midnight and 0800 h in the majority of women, (2) luteinization of the granulosa cells within the pre-ovulatory follicle occurs in response to the LH surge, (3) the increase in prolactin at the time of the LH surge is not directly related to increasing levels of oestradiol but may be due to a decrease in hypothalamic inhibition of prolactin secretion which occurs coincident with the release of LHRH associated with the preovulatory LH surge.     

GONADOTROPHIN SECRETION IN THE SECOND HALF OF THE MENSTRUAL CYCLE: A COMPARISON OF WOMEN WITH NORMAL CYCLES, LUTEAL PHASE DEFECTS AND DISTURBED FOLLICULAR DEVELOPMENT

In order to study the relationship between episodic gonadotrophin secretion and alterations of ovarian hormone secretion, we examined women with normal menstrual cycles (n = 26), luteal phase defects (n = 10) or disturbed follicular oestradiol secretion (n = 8) as established by daily (except weekends) determinations of oestradiol and progesterone. Pulsatile gonadotrophin secretion was studied during the luteal phase or the second half of the menstrual cycle sampling at 15 min intervals for 12 h. LH and FSH mean concentrations and LH pulse frequency were significantly (P less than 0.01) increased in the group with disturbed follicular development in the presence of decreased oestradiol (E2) and progesterone (P4) levels. In women with luteal phase defects mean LH and FSH concentrations and pulsatile LH secretion showed a nonsignificant trend to lower values in the presence of significantly decreased P4 concentrations during the luteal phase.     

Effect of exposure to long days on the secretion of oestradiol, oestrone, progesterone, testosterone, androstenedione, cortisol and follicle-stimulating hormone in intact and spayed ferrets

The changes in concentration of plasma oestradiol, oestrone, progesterone, androstenedione, testosterone, cortisol and FSH were followed in intact female ferrets brought into oestrus by extension of the photoperiod from 8 to 16 h daily. An additional group of spayed females was similarly exposed to the extended photoperiod. There was no change in the blood oestrone, androstenedione and testosterone levels in the spayed females; the concentration of oestradiol, progesterone and FSH fell, while that of cortisol rose after 6 weeks. The intact females showed no change in plasma oestrone and cortisol concentrations, a rise in plasma oestradiol associated with the onset of oestrus, and falls in the blood levels of testosterone, androstenedione, progesterone and FSH. These results indicate that the changes in plasma gonadal steroid levels after extension of the photoperiod differ markedly from those in rodents or ruminants.     

Pituitary function in patients with newly diagnosed untreated systemic lupus erythematosus

OBJECTIVES: To determine whether hormonal dysfunction involving the hypothalamic-pituitary-adrenal (HPA) axis, prolactin (PRL) secretion, and sex hormone status contribute to development of systemic lupus erythematosus (SLE). METHODS: 11 patients with SLE and 9 healthy controls were tested for their total anterior pituitary gland reserve by simultaneous injection of corticotropin-, growth hormone- (GH), thyrotropin-, and gonadotropin-releasing hormone (GnRH). Serum concentrations of adrenocorticotropin (ACTH), cortisol, GH, thyroid stimulating hormone (TSH), PRL, luteinising hormone (LH), and follicle stimulating hormone (FSH) were measured at baseline and after injection. Baseline values of oestradiol, testosterone, and thyroxine were determined. RESULTS: Basal and stimulated serum concentrations of ACTH, cortisol, GH, and PRL were similar in both groups. In contrast, despite similar basal thyroxine levels the TSH response to TRH was significantly higher in patients than in controls. LH and FSH levels in premenopausal female patients of both groups were identical. In contrast, two of the three male patients were hypogonadal without compensatory increases of basal LH and FSH levels, but they retained excessive stimulatory capacity in response to GnRH. CONCLUSION: No significant alteration of the HPA axis was found in patients with SLE, which is inadequate in view of the continuing inflammation. GH and PRL secretion were normal. The pituitary-thyroid and pituitary-gonadal axes were affected in patients with newly diagnosed, untreated SLE.     

Bone turnover and hormonal perturbations in patients with fibromyalgia

OBJECTIVE: Studies of bone turnover in fibromyalgia (FM) have, to date, shown conflicting results. Although most patients with FM are women, only a few investigations have paid attention to the changes of sex hormones in FM. Moreover, FM is often viewed as a stress related disorder, and abnormalities of the hypothalamic-pituitary-adrenal (HPA) axis have been found in FM. The aim of the study was to assess bone turnover using serum osteocalcin and CTx in patients with FM and study correlation between bone turnover parameters and parathormon and hormones of the HPA axis. METHODS: A total of 81 subjects participated in this study: 41 healthy volunteers and 40 patients with FM. Serum osteocalcin, crosslaps (C-telopeptide: CTx), parathyroid hormone (PTH), testosterone, estrogen, prolactin, FSH, and LH were measured. The mean age of the study population was 49.5 (7.6) years (32-69) and the mean disease duration was 8.1 (12.0) years (4.5-30.7). RESULTS: No difference between patients and controls were observed in serum calcium, phosphorus, creatinine, albumin, osteocalcin, testosterone, and urinary calcium. Patients had lower serum levels of CTx, estrogen, PTH and prolactin than controls and higher serum levels of LH and FSH with a significant statistical difference. No significant statistical correlation was observed between intensity of pain and fatigue and bone turnover parameters and PTH or hormones of the HPA axis. CONCLUSION: Our study showed that patients with FM had low bone resorption and normal bone formation compared to a control group. This was not related to several hormonal perturbations observed in these patients and may reflect functional impairment as suggested in previous studies.     

Purified FSH stimulates production of inhibin by the human ovary

Ovarian inhibin production is stimulated by the administration of human menopausal gonadotrophins or following a rise in endogenous LH and FSH. In order to determine whether FSH specifically stimulates inhibin secretion in vivo, immunoassayable serum inhibin levels were measured following the administration of a highly purified preparation of urinary FSH free of significant contamination with LH. Ten anovulatory women underwent a protocol of induction of ovulation with purified FSH and human chorionic gonadotrophin (hCG). During the induction of ovulation, blood samples were taken for radioimmunoassay of FSH, LH, oestradiol, progesterone and inhibin. During the administration of FSH there were increases in plasma concentrations of FSH, oestradiol and inhibin (P less than 0.01) but no significant change in the concentration of LH. Oestradiol and inhibin concentrations rose in parallel and were closely correlated (tau = 0.920, n = 110, P less than 0.001). There was also a direct correlation between the measured level of FSH and inhibin (tau = 0.512, n = 110, P less than 0.05), but there was no correlation between LH and oestradiol, inhibin or FSH. Inhibin (tau- = 0.702, n = 10, P less than 0.01) and oestradiol (tau- = 0.691, n = 10, P less than 0.01) were correlated with the number of follicles seen on ovarian ultrasound. Levels of oestradiol and inhibin reached a peak on the day of hCG administration or on the following day. Inhibin levels then fell over the next 2 days in all cycles. In an ovulatory cycle resulting in conception, inhibin and oestradiol then rose in parallel with progesterone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Endocrine status in stage II vs. advanced premenopausal and postmenopausal breast cancer patients.

Circulating preoperative levels of DHEA-S, androstenedione and SHBG were measured in 40 premenopausal and 49 postmenopausal breast cancer patients, and in 30 and 15 age-matched healthy controls, respectively. Moreover, the levels of LH, FSH, prolactin, estradiol, progesterone, testosterone, DHEA-S, androstenedione and SHBG of Stage II breast cancer patients were compared with advanced patients and also with controls. In premenopausal patients the levels of steroid hormones were significantly low whereas those of peptide hormones were significantly high. On the contrary, in postmenopausal patients, except DHEA-S, all other hormones were significantly elevated in comparison with controls. In premenopausal patients, DHEA-S, androstenedione, estradiol, progesterone, and testosterone decreased as stage advanced with concomitant increase of SHBG, LH, FSH and prolactin when compared with hormone levels of Stage II patients. In postmenopausal advanced breast cancer patients, when compared with Stage II patients, the levels of SHBG, LH, FSH, and prolactin increased significantly, while DHEA-S, androstenedione, estradiol, and progesterone decreased as stage advanced.     

The pituitary-gonadal axis in women with benign or malignant ovarian tumors.

The serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), human chorionic gonadotropin (hCG), estradiol, progesterone, androstenedione, testosterone (total and free) and dehydroepiandrosterone sulphate (DHEAS) were investigated prior to surgery in 24 postmenopausal women with benign and 28 postmenopausal women with malignant epithelial ovarian tumors. The serum concentrations of hormones were compared with those of 28 healthy, postmenopausal, age-matched controls. Significantly lower serum FSH levels were demonstrated in women with malignant tumors. No significant differences were found between the groups regarding the serum LH levels. The hCG levels were low in all groups. Regarding progesterone and estradiol levels, low postmenopausal steroid levels were found in all groups examined and no significant differences were demonstrated within the groups. No significant correlations between the levels of estradiol and FSH or progesterone and LH were demonstrated. To exclude a central depression of gonadotropin release mediated by the dopaminergic system we examined the thyroid stimulating hormone (TSH) and prolactin. No differences were found between the groups regarding TSH and prolactin levels. A possible relationship between other hormones/factors produced by the tumor and exerting a negative feedback, either centrally or directly, on the gonadotropin release remains to be investigated. A change in biological activity in the gonadotropins might explain the present findings.     

Peptide and steroid hormone levels in pre- and postmenopausal breast carcinoma

Circulating levels of LH, FSH, prolactin, estradiol, progesterone and testosterone were measured by radioimmunoassay in 15 premenopausal (PR-M) age matched healthy controls, 35 premenopausal breast cancer patients prior to therapy, 20 postmenopausal (PO-M) age matched healthy controls and 68-71 postmenopausal breast cancer patients prior to therapy. The patients had histologically proven breast cancer. In PR-M breast cancer group, the LH and progesterone did not differ significantly whereas prolactin showed marked elevation (p less than 0.001) and estradiol and testosterone showed significant decrease (p less than 0.001). The PO-M breast cancer patients exhibited remarkable increase in the levels of LH, FSH, prolactin and testosterone (p less than 0.001) whereas estradiol and progesterone showed little increase in the levels (p less than 0.2 and less than 0.1, respectively). From the results, it is concluded that prolactin and altered ratio of estrogen and androgen plays a major role in the genesis of breast cancer.     

Changes in follicle-stimulating hormone, luteinizing hormone, prolactin, oestradiol and progesterone concentrations in the sera of anovulatory androgenized female and castrated male parabiotic rats of the Fischer-344 strain

The serum concentrations of FSH, LH and prolactin, as well as oestradiol and progesterone, were measured by immunoassays at various intervals up to 35 weeks after parabiotic union of an anovulatory androgenized female and a castrated male rat of the Fischer-344 strain. Modest increases in FSH (28%) and larger increases in LH (128%), compared to levels found in single adult animals, produced large increases in follicular growth, ovarian weight and oestrogen production in the female partners; thecal and interstitial elements of the ovaries were not heavily stimulated. Prolactin concentrations in the sera increased to exceedingly high levels and massive pituitary tumours were produced in all of the female partners. Development of cystic follicles with loss of granulosa-cell layers and the formation of early stages of granulosa-cell tumours progressed with time in union. Serum LH levels were as high in parabiotic as in single castrated male rats within 2 weeks, but concentrations of FSH remained much below those of the single animals until 27 weeks after castration. The results are consistent with the view that the ovaries of androgenized female rats of the Fischer strain produce some factor which prevents the post-castration rise in FSH of parabiotic male partners.     

Sex hormone status in women suffering from rheumatoid arthritis

We studied the sex hormone status of 21 seropositive (IgM-RF) women with rheumatoid arthritis (RA), who were subdivided according to their premenopausal and postmenopausal status. Age matched women with secondary osteoarthritis were used as controls. The hormones evaluated were luteinizing hormone (LH), follicle stimulating hormone (FSH), prolactin (PRL), 17-beta-estradiol (E2), progesterone (Pg), testosterone (T), delta 4-androstenedione (A), dehydrotestosterone (DHT), dehydroepiandrosterone sulphate (DHEAS) and cortisol (C). Normal concentrations of all the hormones considered were found in premenopausal women with RA. Statistically higher concentrations of T (p less than 0.05), A (p less than 0.05) and DHEAS (p less than 0.01) were observed in postmenopausal women with RA when compared to controls, whereas no differences were found for all other hormones studied. Although the significance of observed relative hyperandrogenism in postmenopausal women with RA is not clear, our data seem to indicate that sex hormone levels are altered in patients with RA.     

Effect of epidermal growth factor on reproductive function of ewes

Adult Merino ewes were infused via the jugular vein with either saline (n = 5) or epidermal growth factor (EGF) (4.2 micrograms/kg per h, n = 6) for 24 h in either the luteal phase or the follicular phase of the oestrous cycle and reproductive function was examined. Infusion of EGF during the luteal phase caused no detectable change in plasma progesterone or prolactin concentrations over a 7-day period compared with the controls. Infusion of EGF during the follicular phase suppressed the oestrous rise in plasma oestradiol. Luteinizing hormone pulse amplitude was increased and pulse frequency was decreased by the end of the infusion. All control ewes had a pro-oestrous LH surge and mated, but the LH surge and oestrus were prevented by EGF infusion. Nevertheless, plasma progesterone levels rose subsequently in the EGF-infused ewes in parallel with the control ewes, suggesting that the preovulatory follicle had luteinized. Both LH and FSH rose over the 7 days after EGF infusion to levels similar to those in ovariectomized ewes. Thus EGF appears to inhibit follicular oestradiol production, although it does not affect luteal progesterone production or follicular luteinization. We suggest that the alteration in gonadotrophin secretion patterns results from a disturbance of feedback mechanisms between the ovary and the hypothalamopituitary axis, although a direct effect in the brain or the pituitary gland cannot yet be excluded.     

Melatonin levels in women with fibromyalgia and chronic fatigue syndrome

OBJECTIVE: Fibromyalgia (FM) and chronic fatigue syndrome (CFS) are stress associated disorders mainly affecting women. FM is characterized primarily by widespread musculoskeletal pain, and CFS by profound debilitating fatigue, but there is considerable overlap of clinical symptoms between these 2 syndromes. Neuroendocrine abnormalities have been noted in both FM and CFS and desynchronization of circadian systems has been postulated in their etiology. The pineal hormone melatonin is involved in synchronizing circadian systems and the use of exogenous melatonin has become widespread in patients with FM and CFS. METHODS: We examined the characteristics and relationship of melatonin and cortisol levels in premenopausal women with FM (n = 9) or CFS (n = 8), compared to age and menstrual cycle phase matched controls. Blood was collected from an indwelling intravenous catheter every 10 min over 24 h, and plasma melatonin and cortisol were determined by radioimmunoassay at 60 and 10 min intervals, respectively. RESULTS: Night time (23:00-06:50) plasma melatonin levels were significantly higher in FM patients compared to controls (p<0.05), but there was no significant difference in melatonin levels between CFS patients and controls. No differences in the timing of cortisol and melatonin secretory patterns and no internal desynchronization of the 2 rhythms were found in either patient group, compared to controls. CONCLUSION: Raised plasma melatonin concentrations have been documented in several other conditions that are associated with dysregulation of neuroendocrine axes. Increased melatonin levels may represent a marker of increased susceptibility to stress induced hypothalamic disruptions. These data indicate that there is no rationale for melatonin replacement therapy in patients with FM and CFS.     

Preliminary endocrinological evaluation of a sustained-release formulation of the LH-releasing hormone agonist D-Ser(But)6Azgly10LHRH in premenopausal women with advanced breast cancer

Twenty-four premenopausal women with advanced breast cancer were treated with a sustained-release (depot) formulation containing 3.6 mg of the LH-releasing hormone agonist D-Ser(But)6Azgly10 LHRH (ICI 118630), given s.c. every 4 weeks for periods of up to 5 months. Although ICI 118630 initially stimulated LH and FSH secretion, serum gonadotrophin concentrations were suppressed on continued treatment. Increased LH and FSH concentrations were associated with relatively normal ovarian activity during the first month of treatment, but low progesterone concentrations were found in all patients thereafter. In 22 out of 24 women, oestradiol concentrations fell during the second month to values equivalent to those observed in oophorectomized or postmenopausal women. In two patients, persistent but reduced oestradiol production was recorded throughout. No appreciable side-effect of the drug was observed.