scholarly journals Effects of hyperandrogenemia and increased adiposity on reproductive and metabolic parameters in young adult female monkeys

2014 ◽  
Vol 306 (11) ◽  
pp. E1292-E1304 ◽  
Author(s):  
W. K. McGee ◽  
C. V. Bishop ◽  
C. R. Pohl ◽  
R. J. Chang ◽  
J. C. Marshall ◽  
...  

Many patients with hyperandrogenemia are overweight or obese, which exacerbates morbidities associated with polycystic ovary syndrome (PCOS). To examine the ability of testosterone (T) to generate PCOS-like symptoms, monkeys received T or cholesterol (control) implants ( n = 6/group) beginning prepubertally. As previously reported, T-treated animals had increased neuroendocrine drive to the reproductive axis [increased luteinizing hormone (LH) pulse frequency] at 5 yr, without remarkable changes in ovarian or metabolic features. To examine the combined effects of T and obesity, at 5.5 yr (human equivalent age: 17 yr), monkeys were placed on a high-calorie, high-fat diet typical of Western cultures [Western style diet (WSD)], which increased body fat from <2% (pre-WSD) to 15–19% (14 mo WSD). By 6 mo on WSD, LH pulse frequency in the controls increased to that of T-treated animals, whereas LH pulse amplitude decreased in both groups and remained low. The numbers of antral follicles present during the early follicular phase increased in both groups on the WSD, but maximal follicular size decreased by 50%. During the late follicular phase, T-treated females had greater numbers of small antral follicles than controls. T-treated monkeys also had lower progesterone during the luteal phase of the menstrual cycle. Although fasting insulin did not vary between groups, T-treated animals had decreased insulin sensitivity after 1 yr on WSD. Thus, while WSD consumption alone led to some features characteristic of PCOS, T + WSD caused a more severe phenotype with regard to insulin insensitivity, increased numbers of antral follicles at midcycle, and decreased circulating luteal phase progesterone levels.

1990 ◽  
Vol 126 (3) ◽  
pp. 385-393 ◽  
Author(s):  
B. K. Campbell ◽  
G. E. Mann ◽  
A. S. McNeilly ◽  
D. T. Baird

ABSTRACT The pattern of pulsatile secretion of inhibin, oestradiol and androstenedione by the ovary at different stages of the oestrous cycle in sheep was studied in five Finn–Merino ewes in which the left ovary had been autotransplanted to the neck. The ewes had jugular venous blood samples collected at 4-hourly intervals from 42 h before the induction of luteolysis by i.m. injection of cloprostenol (100 μg) on day 10 of the oestrous cycle, until day 3 of the following cycle. There were five periods of intensive blood sampling, when both ovarian and jugular venous blood samples were collected, as follows: (a) mid-luteal phase, before the second injection of cloprostenol on day 10 (15-min intervals for 6 h); (b) early follicular phase, 24 h after the second injection of cloprostenol (10-min intervals for 4 h); (c) late follicular phase, 48 h after the second injection of cloprostenol (10-min intervals for 4 h); (d) after the LH surge on day 1 of the cycle, 76 h after the second injection of cloprostenol (10-min intervals for 4 h); (e) early luteal phase on day 3 of the cycle, 120 h after the second injection of cloprostenol (10-min intervals for 3 h). Plasma was collected and the samples assayed for LH, FSH, progesterone, oestradiol, androstenedione and inhibin. The ovarian secretion rates for oestradiol, androstenedione and inhibin were calculated. All ewes responded normally to the luteolytic dose of cloprostenol with the preovulatory surge of LH occurring within 56·4±1·6 h (mean ± s.e.m.) followed by the establishment of a normal luteal phase. The pulse frequency of LH, oestradiol and androstenedione increased in the transition from the luteal to the follicular phase (P<0·01). On day 1 of the cycle LH secretion consisted of low-amplitude high-frequency pulses (1·0±0·1 pulse/h) to which androstenedione, but not oestradiol, responded. On day 3 of the cycle LH secretion was similar to that on day 1 but both androstenedione and oestradiol secretion were pulsatile in response to LH, indicating the presence of oestrogenic follicles. The stage of the cycle had no significant effects on LH pulse amplitude and nadir but the ovarian secretory response to LH stimulation did vary with the stage of the cycle. Prolactin pulse frequency, amplitude and nadir were higher (P<0·05) during the follicular phase than the luteal phase. Prolactin pulse frequency was depressed (P<0·05) on day 1 of the cycle but increased to follicular phase levels on day 3. Prolactin pulse frequency was significantly correlated to oestradiol pulse frequency (r = 0·54; P<0·01). During the luteal phase there were insufficient oestradiol pulses to obtain an estimate of pulse amplitude and nadir but both these parameters reached their highest level during the late follicular phase, fell to negligible levels on day 1 and increased to early follicular phase levels on day 3. Androstenedione pulse amplitude and nadir exhibited similar but less marked variation. Inhibin secretion was episodic at all stages of the cycle examined but did not exhibit significant variation with stage of cycle in any of the parameters of episodic secretion measured. Inhibin pulses were not related to either LH or prolactin at any stage of the cycle. FSH secretion was not detectably pulsatile but jugular venous concentrations of FSH at each stage of the oestrous cycle were negatively correlated with mean oestradiol (r= −0·52; P<0·01 but not inhibin secretion (r = 0·19). We conclude that (i) LH secretion is pulsatile at all stages of the oestrous cycle but the steroidogenic responses of the ovary varies with the stage of the cycle, reflecting changes in characteristics of the follicle population, (ii) ovarian inhibin secretion is episodic and displays little change with the stage of the oestrous cycle and (iii) episodic inhibin secretion is not related to either pulses of LH or prolactin. The aetiology of these inhibin pulses therefore remains unknown. Journal of Endocrinology (1990) 126, 385–393


1989 ◽  
Vol 120 (3) ◽  
pp. 497-502 ◽  
Author(s):  
S. M. Rhind ◽  
S. McMillen ◽  
W. A. C. McKelvey ◽  
F. F. Rodriguez-Herrejon ◽  
A. S. McNeilly

ABSTRACT The effects of body fat content (body condition) of ewes on hypothalamic activity and gonadotrophin-releasing hormone (GnRH) secretion and on pituitary sensitivity to GnRH were investigated using Scottish Blackface ewes. Two groups of 12 ewes were fed so that they achieved either a high body condition score (2·98, s.e.m. = 0·046; approximately 27% of empty body weight as fat) or a low body condition score (1·94, s.e.m. = 0·031; approximately 19% of empty body weight as fat) by 4 weeks before the period of study. Thereafter, they were differentially fed so that the difference in mean condition score was maintained. Oestrus was synchronized, and on day 11 of the subsequent cycle half of the ewes of each group were ovariectomized. On day 12, the remaining ewes were injected (i.m.) with 100 μg prostaglandin F2α analogue and ovariectomized 30 h later. Numbers of large ovarian follicles and corpora lutea present at ovariectomy were recorded. Blood samples were collected at 15-min intervals for 12 h on day 10 of the cycle (luteal phase) and at 10-min intervals from 24 to 30 h after prostaglandin injection (follicular phase). At days 2 and 7 after ovariectomy, samples were collected at 15-min intervals for 8 h and ewes were then injected with 10 μg GnRH and samples were collected for a further 3 h. Samples were assayed for LH and FSH. Ewes in high body condition had more more large follicles than ewes in low body condition during the luteal phase (15·3 vs 6·5; P < 0·05) and follicular phase (11·5 vs 7·0; NS) and a slightly higher mean ovulation rate (1·50 vs 1·20; NS). However, during the luteal and follicular phases of the cycle before ovariectomy there was no effect of condition score on mean LH or FSH concentrations or mean LH pulse frequency or pulse amplitude. Two days after ovariectomy, ewes of high body condition had a higher mean LH pulse frequency than ewes of low body condition (P < 0·05) and higher mean FSH concentrations (P < 0·05). Mean LH concentration and pulse amplitude were not affected. LH and FSH profiles were not affected by body condition on day 7. GnRH-induced increases in LH and FSH concentrations on days 2 and 7 were not affected by body condition. At day 7, but not day 2, ewes ovariectomized during the luteal phase of the cycle had a significantly (P < 0·05) greater GnRH-induced LH release compared with ewes ovariectomized during the follicular phase. It is concluded that body condition directly affects hypothalamic activity and GnRH secretion, but not pituitary sensitivity to GnRH, and that effects on reproductive performance are also mediated through changes in ovarian hormones or in hypothalamo-pituitary sensitivity to ovarian hormones. Journal of Endocrinology (1989) 120, 497–502


1985 ◽  
Vol 107 (3) ◽  
pp. 429-436 ◽  
Author(s):  
G. Shaw ◽  
G. I. Jorgensen ◽  
R. Tweedale ◽  
M. Tennison ◽  
M. J. Waters

ABSTRACT Adult Merino ewes were infused via the jugular vein with either saline (n = 5) or epidermal growth factor (EGF) (4·2 μg/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. J. Endocr. (1985) 107, 429–436


1988 ◽  
Vol 116 (1) ◽  
pp. 123-135 ◽  
Author(s):  
J. M. Wallace ◽  
G. B. Martin ◽  
A. S. McNeilly

ABSTRACT It has previously been shown that treatment of ewes with bovine follicular fluid (bFF) throughout the luteal phase of the oestrous cycle lowers plasma levels of FSH but increases the frequency and amplitude of the pulses of LH. Under these conditions, ovarian follicles grow to a maximum diameter of 2·7 mm and have a reduced capacity to release oestradiol. We have examined the nature of the gonadotrophin signals controlling follicular development in the normally cycling ewe and have investigated the effects of previous exposure to bFF on these signals and the follicular responses to them. Control ewes (n = l) were injected i.v. with 9 ml bovine serum and treated ewes were injected with 9 ml bFF, twice daily from days 1 to 10 of the luteal phase (day 0 = oestrus). The ewes were injected with prostaglandin analogue on day 11 of the cycle to induce luteolysis and the gonadotrophin patterns were studied in blood sampled from these animals every 10 min for up to 72 h during the subsequent follicular phase. Following luteolysis (and the end of bFF treatment), LH pulse frequency increased rapidly in both groups and reached 1 pulse/h within 6 h. Thereafter, pulse frequency increased marginally and reached 1 pulse/50 min by the onset of the LH surge. This pattern was not affected by previous treatment with bFF. In the control ewes, the amplitude of the LH pulses did not change significantly following luteolysis or at any time during the follicular phase, while the levels of FSH declined slowly until the onset of the surge. In the treated ewes, on the other hand, there was an immediate increase in both LH pulse amplitude and the concentration of FSH immediately after the end of bFF treatment at luteolysis, and they remained above control levels for 24 and 16 h respectively. Plasma prolactin levels did not appear to change around the time of luteolysis but showed a marked and significant diurnal rhythm (nadir around noon and peak around midnight) in both groups. The concentrations of prolactin were significantly (P<0·001) lower and the preovulatory peak was delayed and reduced in the bFF-treated ewes relative to controls. The onset of oestrus was also significantly (P<0·01) delayed by bFF treatment, but the ovulation rates did not differ between the groups. Furthermore, comparisons within or between groups revealed no significant relationships between any of the variables of plasma LH secretion during the follicular phase and the subsequent ovulation rate. These observations provide a complete description of gonadotrophin patterns during the follicular phase of the ewe and confirm the suggestion that an increase in LH pulse frequency is the major driving force behind the follicular growth that ultimately leads to ovulation. On the other hand, it appears most unlikely that the pattern of LH secretion during the follicular phase has any influence on ovulation rate. The levels of FSH declined in the period leading up to the preovulatory surge, presumably as a consequence of rising peripheral levels of oestrogen (and/or inhibin). We also expected LH pulse amplitude to decline during the follicular phase because it has been proposed that pulse amplitude is also controlled by oestrogen. The absence of any significant fall in amplitude suggests that hypotheses about the control of LH secretion drawn from studies with ovariectomized ewes require further verification in the intact ewe. The effect of bFF on prolactin levels probably reflects the low rates of secretion of oestradiol by the small ovarian follicles in these ewes. J. Endocr. (1988) 116, 123–135


1989 ◽  
Vol 122 (2) ◽  
pp. 509-517 ◽  
Author(s):  
R. J. E. Horton ◽  
H. Francis ◽  
I. J. Clarke

ABSTRACT The natural opioid ligand, β-endorphin, and the opioid antagonist, naloxone, were administered intracerebroventricularly (i.c.v.) to evaluate effects on LH secretion in ovariectomized ewes and in ovariectomized ewes treated with oestradiol-17β plus progesterone either during the breeding season or the anoestrous season. Ovary-intact ewes were also studied during the follicular phase of the oestrous cycle. Jugular blood samples were taken at 10-min intervals for 8 h and either saline (20–50 μl), 100 μg naloxone or 10 μg β-endorphin were injected i.c.v. after 4 h. In addition, luteal phase ewes were injected i.c.v. with 25 μg β-endorphin(1–27), a purported endogenous opioid antagonist. In ovariectomized ewes, irrespective of season, saline and naloxone did not affect LH secretion, but β-endorphin decreased the plasma LH concentrations, by reducing LH pulse frequency. The effect of β-endorphin was blocked by administering naloxone 30 min beforehand. Treating ovariectomized ewes with oestradiol-17β plus progesterone during the breeding season reduced plasma LH concentrations from 6–8 μg/l to less than 1 μg/l. In these ewes, saline did not alter LH secretion, but naloxone increased LH pulse frequency and the plasma concentrations of LH within 15–20 min. During anoestrus, the combination of oestradiol-17β plus progesterone to ovariectomized ewes reduced the plasma LH concentrations from 3–5 μg/l to undetectable levels, and neither saline nor naloxone affected LH secretion. During the follicular phase of the oestrous cycle, naloxone enhanced LH pulse frequency, which resulted in increased plasma LH concentrations; saline had no effect. In these sheep, β-endorphin decreased LH pulse frequency and the mean concentrations of LH, and this effect was prevented by the previous administration of naloxone. The i.c.v. administration of β-endorphin(1–27) to luteal phase ewes did not affect LH secretion. These data demonstrate the ability of a naturally occurring opioid peptide to inhibit LH secretion in ewes during the breeding and non-breeding seasons, irrespective of the gonadal steroid background. In contrast, whilst the gonadal steroids suppress LH secretion in ovariectomized ewes during both seasons, they only appear to activate endogenous opioid peptide (EOP)-mediated inhibition of LH secretion during the breeding season. Furthermore, these data support the notion that LH secretion in ovariectomized ewes is not normally under the control of EOP, so that naloxone has no effect. Journal of Endocrinology (1989) 122, 509–517


Endocrinology ◽  
2013 ◽  
Vol 154 (11) ◽  
pp. 4249-4258 ◽  
Author(s):  
Casey C Nestor ◽  
Lique M. Coolen ◽  
Gail L. Nesselrod ◽  
Miro Valent ◽  
John M. Connors ◽  
...  

Orphanin FQ (OFQ), a member of the opioid family, is found in many areas of the hypothalamus and, when given centrally OFQ inhibits episodic LH secretion in rodents and sheep. Because GnRH neurons are devoid of the appropriate receptors to mediate steroid negative feedback directly, neurons that release OFQ may be involved. Using immunocytochemistry, we first determined that most OFQ neurons in the arcuate nucleus (ARC) and other hypothalamic regions of luteal phase ewes contained both estrogen receptor α and progesterone (P) receptor. Given a similar high degree of steroid receptor colocalization in other ARC subpopulations, we examined whether OFQ neurons of the ARC contained those other neuropeptides and neurotransmitters. OFQ did not colocalize with kisspeptin, tyrosine hydroxylase, or agouti-related peptide, but all ARC OFQ neurons coexpressed proopiomelanocortin. To test for a role for endogenous OFQ, we examined the effects of an OFQ receptor antagonist, [Nphe1,Arg14,Lys15]Nociceptin-NH2 (UFP-101) (30 nmol intracerebroventricular/h), on LH secretion in steroid-treated ewes in the breeding season and ovary-intact ewes in anestrus. Ovariectomized ewes with luteal phase concentrations of P and estradiol showed a significant increase in LH pulse frequency during infusion of UFP-101 (4.5 ± 0.5 pulses/6 h) compared with saline infusion (2.6 ± 0.4 pulses/6 h), whereas ewes implanted with only estradiol did not. Ovary-intact anestrous ewes displayed no significant differences in LH pulse amplitude or frequency during infusion of UFP-101. Therefore, we conclude that OFQ mediates, at least in part, the negative feedback action of P on GnRH/LH pulse frequency in sheep.


1977 ◽  
Vol 85 (1) ◽  
pp. 177-188 ◽  
Author(s):  
Sten Jeppsson ◽  
Gunnar Rannevik ◽  
Jan I. Thorell

ABSTRACT A longitudinal study of basal plasma LH and FSH and their responses to 25 μg LRH iv as well as basal levels of oestradiol, progesterone, prolactin and HCG was performed every week in 3 women, pregnant after heterologous insemination, from conception until the 6th week of gestation. A comparative study was carried out in 7 women in cycles in which no conception occurred after insemination. All hormones were assayed with radioimmunoassay. LH was measured with a specific assay for native LH, which did not cross-react with HCG. A decrease in basal levels of LH and FSH as well as decreasing responses to LRH was found during the first 2 weeks of gestation. These changes did not differ from what was observed during the luteal phase in the non-conception cycles. One week later the basal FSH levels and the FSH response in the pregnant women showed a further decrease, while in the non-pregnant women, now reaching the early follicular phase, a rise in FSH basal levels occurred. The basal levels of LH and the LH response, however, did not differ from that found in the nonpregnant women at this time. FSH basal levels remained below the lower normal limit in eumenorrhoic women from the 3rd week of gestation. By this time the FSH response was almost completely inhibited. The LH basal levels, however, remained above the lower normal limit in eumenorrhoic women, but the LH response to LRH progressively decreased and was completely inhibited by the 5th week of gestation. In the non-conception cycles the LH response varied with the levels of oestradiol in plasma. This was not found in the pregnant women as the decrease in gonadotrophin response occurred while oestradiol remained at mid-cycle levels during the first 4 weeks of gestation. Rather it seems that the increasing and continuously elevated level of progesterone, in the presence of appropriate levels of oestradiol, might be the main go nadal steroid responsible for the diminishing pituitary secretion. The contribution of HCG to the further decrease in gonadotrophin secretion after the 2nd week of pregnancy cannot be answered by the present studies. Prolactin remained at non-pregnant levels until the 6th week of gestation, and appeared to have no influence on the secretion of gonadotrophins during early pregnancy.


2002 ◽  
pp. 347-356 ◽  
Author(s):  
AD Genazzani ◽  
M Luisi ◽  
B Malavasi ◽  
C Strucchi ◽  
S Luisi ◽  
...  

OBJECTIVE: To investigate whether allopregnanolone, a neuroactive steroid involved in modulating behavioural and neuroendocrine functions, shows episodic secretion in eumenorrheic women, during the follicular and luteal phases of the menstrual cycle, and in women with stress-induced amenorrhea. PATIENTS: Six eumenorrheic women and 14 women with hypothalamic amenorrhea were enrolled for the present study. METHODS: All subjects underwent hormonal evaluation in baseline conditions and a pulsatility study to determine LH, cortisol and allopregnanolone episodic release. Eumenorrheic subjects were investigated twice, in the follicular phase (days 3-7) and in the luteal phase (days 18-22) of the menstrual cycle. LH, FSH, prolactin, estradiol, phosphate, DHEA, allopregnanolone and cortisol levels were evaluated in each case. RESULTS: In healthy women, serum gonadotropin and gonadal steroid levels were significantly lower (P<0.01 and P<0.05 respectively) than those in amenorrheic subjects. Allopregnanolone was higher in amenorrheic subjects and during the luteal phase, compared with the follicular phase, of eumenorrheic subjects (P<0.01). Pulse analysis revealed a significant episodic discharge of allopregnanolone in all subjects (follicular phase 6.5+/-0.3 peaks/6 h and luteal phase 5.5+/-0.4 peaks/6 h, hypothalamic amenorrhea 7.0+/-0.7 peaks/6 h) with higher pulse amplitude in amenorrheic subjects and during the luteal phase compared with the follicular phase of the eumenorrheic subjects (P<0.05). Moreover, the specific concordance index demonstrated that allopregnanolone is coupled with LH only during the luteal phase of the cycle and with cortisol during both phases. Allopregnanolone-cortisol coupling was also observed in amenorrheic subjects. CONCLUSIONS: Allopregnanolone is secreted episodically. Both the ovary and adrenal glands release this steroid hormone and it shows temporal coupling with LH only during the luteal phase, with cortisol during both the studied phases of the menstrual cycle in eumenorrheic women and again with cortisol in hypothalamic amenorrheic patients.


1989 ◽  
Vol 123 (2) ◽  
pp. 181-188 ◽  
Author(s):  
G. E. Mann ◽  
A. S. McNeilly ◽  
D. T. Baird

ABSTRACT The source of inhibin secretion by the ovary in the sheep at different stages of the oestrous cycle was investigated by in-vivo cannulation of the ovarian veins. Twenty-four Scottish Blackface ewes were allocated to four groups of six ewes, i.e. those operated on during the luteal phase (day 10), and those operated on during the follicular phase 24–30, 36 and 60 h following an injection of 125 μg cloprostenol on day 10 of the luteal phase. Samples of jugular and timed ovarian venous blood were collected under anaesthesia before and after enucleation of the corpus luteum. Ovaries were then removed and follicles dissected out. Following injection of cloprostenol, luteal regression occurred as indicated by a fall in the secretion of progesterone. The concentration of inhibin in jugular venous plasma and its ovarian secretion rate were similar at all stages of the follicular phase and during the luteal phase. In contrast, the secretion rate of oestradiol rose from 2·68 ±0·73 pmol/min during the luteal phase to 8·70± 2·24 pmol/min 24 h after injection of cloprostenol (P<0·05). Following enucleation of the corpus luteum the secretion rate of progesterone fell from 809 ± 270 pmol/min to 86 ± 30 pmol/min (P<0·001). There was also a smaller, artifactual fall in the secretion rate of oestradiol following enucleation of the corpus luteum, which was of similar size to a fall seen in the secretion rate of inhibin. This resulted in a significant (P<0·001) fall in the ratio of progesterone to inhibin, while the oestradiol to inhibin ratio remained unchanged. The secretion rate of inhibin from ovaries containing luteal tissue was similar to that from the contralateral side without luteal tissue (1·41±0·30 compared with 1·32±0·30 ng/min), while ovaries with large antral follicles secreted significantly (P< 0·001) more inhibin than those with no follicles ≥3 mm (2·28 ± 0·36 compared with 0·25 ±0·06 ng/min). From these results we conclude that, in the sheep, large antral follicles are responsible for most, if not all, the secretion of inhibin by the ovary at all stages of the oestrous cycle, and that the corpus luteum secretes little or no immunoactive or bioactive inhibin. Due to the fact that, unlike inhibin, the secretion rate of oestradiol rises during the follicular phase of the cycle, when the concentration of FSH is suppressed, it seems likely that oestradiol rather than inhibin is the major ovarian factor modulating the change in FSH secretion seen at this stage of the oestrous cycle. Journal of Endocrinology (1989) 123, 181–188


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