Gynecol. Endocrinol. 5 ( 1 991) 277-288

Neuroendocrine control in polycystic ovary-like syndrome

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J. Schoernaker

Division qf Reproductive Endocrinology and Fertility, Department of Obstetrics and Gynecolog:v, Free Urziversity Hospital, Amsterdam, T h e Netherlands Abstract

In this review article evidence is assembledfrom the neuroendocrinology of women with polycystic ovary-like syndrome (PCOS),to argue that the central dysregulation of gonadotropin secretion as found in the syndrome is not the cause ofits development. The increased amplitude of 1ut:einizing hormone (LH) pulses is explained by an increased pituitary sensitivity to gonadotropin releasing hormone (GnRH)due to prolonged unopposed estrogen exposure ofthe gonadotropic cells. The increase in pulse frequency cannot be used in the argument because it may tie the cause for, as well the result of, the pathologcal status of the ovary. A good argument for a pathogenetic involvement of central factors, however, is the reversed day/night rhythm in adolescent grls with PCOS. A critical review of the literature does not g v e evidence of involvement of either obesity or catecholamines in the central abnormalities. Therefore they cannot cause PCOS via central feedback systems. The response of the gonadotropins to progesterone is the same as it is in normally cycling women. Androgens exert a variable effect on LH secretory patterns, although they do induce the typical change ofPCOS in the ovaries.This argues for an ovarian rather than for a central cause. Endogenous opiates seem to be increased in PCOS. It can be argued that this should suppress both LH secretion and adrenal androgen secretion. It should also stimulate insulin-like growth factor (1GF)binding proteins, thereby binding more IGF with less stimulatory action on the theca cells to produce androgens. Therefore endogenous opiates do not seem to be involved in the pathogenesis of PCOS either. Studies in PCOS during the recovery from GnRH agonist treatment show that the luteinizing hormone/follicle stimulating hormone (LH/ FSH) ratio is quite normal for some time during the recovery phase. Correspondence to J Schoemaker, Division of Reproductive Endocnnology and Fertility, Department of Obstetncs and Gynecology, Free University Hospital, PO Box 7057, 1007 MB Amsterdam,, The Netherlands



Shoemaker However, PCOS always develops again. This therefore does not g v e a clue either.

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In pulsatile GnRH stimulation of PCOS patients, the LH and FSH secretory patterns completely normalize. However, the symptoms of PCOS continue under this stimulation and the clinical pattern does not change dramatically. This gives the best argument that PCOS is caused by one or more peripheral factors, which may be ovarian in origin, rather than by central factors. Introduction

One ofthe most intriguing issues in the pathogenesis ofpolycystic ovary disease (PCOD) is the question of whether the syndrome originates in the ovary or whether the abnormalities in gonadotropin secretion are at the basis of this disease. In this review we will focus on the neuroendocrine mechanisms which control gonadotropin secretion in PCOD and see if we can find arguments to either support or reject the hypothesis that the primary abnormality is the disturbed regulation of gonadotropin secretion.

LH secretion Luteinizing hormone is secreted in a pulsatile fashion'.' under the influence of the pulsatile secretion of luteinizing hormone releasing hormone (LHRH) from the hypothalamus""', which in turn is under the control of a postulated hypothalamic pulse generator".". LHRH pulses evoke a short episode of LH secretion from the pituitary. In addition to the release of LH, LHRH pulses also induce synthesis of new LHt3 as well as a short period of decreased pituitary sensitivity for LHRH1"'j. It is the latter mechanism which may prevent an LH response to a second LHRH pulse if the interval between the two pulses is too short. For this reason a few LH pulses are lost in comparison to LHRH pulses'. LH secretory pulse patterns are characterized by the pulse amplitude, the pulse frequency and the mean LH concentration. Different mathematical methods have been devised to distinguish a real pulse from the fluctuation occurring due to the inaccuracy of the assays (assay-noi~e)'~-~'. The pulse characteristics of women with regular menstrual cycles, particularly during the follicular phase, have been determined by several authors24-?6. The first critical comparison of the characteristics of LH secretion with adequate controls, according to Kazer and colleaguesz5,came from Burger and co-workers26.They very carefully compared the pulse amplitude and the nadir interval, which is the reciprocal of the pulse frequency, in women with polycystic ovary disease, normally cycling women during their follicular phase and women with non-PCOD amenorrhea. They concluded that the amplitude of the pulses in PCOD was 2-3 times the amplitude found during the follicular phase of normally cycling women. The nadir interval in PCOD was slightly shorter, 50 vs. 60 min, and consequently the pulse frequency slightly higher

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than in the follicular phase. Both the increased pulse frequency and the increased pulse amplitude therefore contribute to the elevated LH level, as found in patient5 with polycystic ovary disease. Waldstrcicher and co-workers" confirmed all three changes in characteristics, that is LH level, LH pulse amplitude and LH pulse frequency, as found by Burger and colleagues'". Finally Kazer and colleagues" were able to confimi the data on LH level and pulse amplitude, but were not able to coilfirin the increased pulse frequency. The increased aniplitude is generally believed to be largely caused by the increased sensitivity of the pituitary to L H R H , due to the persistent influence of estrogens'". It cannot. however be ruled out that the amplitude of LHRH pulse5 JF such is increased as well. A change in frequency is considered clear evidence of thc fact that the hypothalanius is involved in the inappropriate gonadotropin secretion in PCOD women. Because of the evidence presented, we do believe that this is the case. Whether this involvement is a primary defect or whethtr it is caused by abnormal hormone secretion from the ovaries and/or thy adrenals remains to be elucidated. O n e argunient that, at least during pubertal development, the hypothalamic pulse generator is intrinsically abnormal is that the diurnal rhythm in adolescent P C O D is reversed, that is, high levels during the day and low levels during the night". This type of secretory pattern, which is normal in the early follicular phase of adult wonicn2', could no longer be demonstrated by Waldstreicher and colleagues-'- in adult I'COI3 women. Obesity

l h n a i f and co-workers" exanlined whether obesity could be one ofthe factors that influenced the neuroendocrinology of either normally cycling or PCOD wonien In comparing obese I'COD women, non-obese PCOD woinen, obese n ortien with normal cycles and non-obese women with normal cycles she failed i:o demonstrate any difference in the niean LH level, the LH pulse frequency the LH pulse amplitude or the integrated LH secretion between obese and non-obae individuals, either in women with normal cycle$, or in PCOD women Progesterone

Minakanii and co-workers'" focused attention 011the clinically well-known fact that LH levels tend to normalize during spontaneous and induced ovulatory cycles in women with PCOD. They followed 33 PCOLI women, taking blood samples at regular intervals and relating the LH levels in those to a spontaneous shift in the basal body temperature curve. By doing so they showed that virtually all LH levels declined till below the upper limit of normalcy during the luteal phase ofthese cycles, the nadir occurring 14 days after the shift, that is at the time of the inemtrual bleeding. After menstruation LH levels started to rise again, all being above the upper limit of normalcy again 14 days after the beginning of

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the menstrual period. They also showed how important it is to determine LH for PCOD diagnosis at least 14 days after the beginning of the last menstrual period. Whether this decrease in LH levels is the result of progesterone alone or is also caused by other ovarian factorsfrom the corpus luteum acting synergstically, remains to be established. Buckler and colleagues3' studied the single effect of progesterone in PCOD women. They administered 50 mg ofprogesterone two times per day, vaginally, for 14 days to anovulatory PCOD women, obtaining plasma progesterone levels comparable to those during a normal luteal phase. The effect on LH levels was an initial rise of approximately 25% followed by a decrease to about 80% of baseline. The LH pulse pattern changed into a typical luteal pattern with a slowing of the LH pulse frequency and an increase in pulse amplitude. However, the LH secretory pattern was higher than normal in the luteal phase. Summarizing the effect of progesterone, it can be stated that this steroid has a normalizing effect on LH secretion probably by influencing both the pituitary sensitivity for LHRH and the hypothalamic pulse generator. The latter obviously reacts in a normal way to progesterone administration, diminishing the likelihood of an intrinsic defect.

Androgens Evidence from the endocrinology of PCOD as such suggests that androgens may play a crucial role in the pathogenesis of inappropriate gonadotropin secretion in this syndrome. Lob0 and Goebelsman3' pointed out the PCOD-like abnormalities in women with enzyme deficiencies leading to increased androgen levels, and Dunaif and colleagues33described a woman with an androgen-producing thecoma and PCOD-like syndrome in whom the disturbance of LH secretion completely disappeared after ovariectomy. However, 2 years after the latter publication, Dunair' published her results of short-term testosterone (T) and &hydrotestosterone (DHT) infusions in women with PCOD. Eight-hour T or DHT infusions failed to influence the LH secretory pattern. Spinder and c o - ~ o r k e r streated ~~ female-to-male transsexuals with high doses of testosterone for at least 6 months and observed a suppression of LH secretion rather than an increase. The ovaries of these transsexuals after T substitution, did show the characteristic histopathological abnormalities of the P C O syndrome. In the same paper, the authors presented further evidence that high androgen levels alone do not necessarily lead to the characteristic LH secretion pattern. A 26-year-old woman, with an androgen-producing tumor of one ovary, showed mildly elevated T levels of 9.6 mmol/l which decreased to 1 mmol/l after removal of the tumor. The pulse pattern, however, was the same before and after the operation and indistinguishable from a normal fohcular phase pattern.

Neirvuendocvine coiitrul


PCOS: R e v i e w

28 1

The conclusion, therefore, must be that, although androgens seem to play a role in the pathogenesis of polycystic ovary disease, their role in inappropriate gonadotropin secretion, at least, does not seem to be a direct one.

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Endogenous opiates

The influence of endogenous opiates in polycystic ovary disease is far from clear. At least three types of effect have been studied. The first and most important is the influence of endogenous opiates directly or indirectly on the secretion of LHRH. Secondly, a n influence via the neuroendocnnology of the adrenal axis is possible and thirdly, insulin secretion appears to be under the influence of endogenous opiates and therefore might exert an action via the regulation of the degree of hyperinsulinemia. As in normal women the endogenous opiates have a suppressing effect on LH ~ecretion'~.'', it was postulated that the elevated LH level in PCOD might be caused by a decreased opiatergc tone. However, Givens and co-workers", already in 1980 had shown that circulating levels of P-endorphin were elevated in PCOD patients. Barnes and Lobo3qperformed naloxone infusions in women with PCOD and in weight-matched normally cycling controls. They showed that the increase in LH was proportionally the same in both groups. Only when they increased the dopaminergc tone in the hypothalamus by the administration of levodopa and carbidopa were they able to show a difference. Levodopalcarbidopa abolished the rise in LH in normally cycling women while in PCOD patients the response even seemed to increase. This at least suggests that the interaction between the dopaminergic and the opiatergic system is different in PCOD. Ambrog,o and co-workers4('examined the role of endogenous opioids in the regulation of the hypothalamo-pituitary-adrenal axis and discovered that naloxone infusion excessively increased dehydroepiandrosterone (DHEA) secretion in patients with € C O D compared to normal controls. They concluded that, at least in the regulation ofthe adrenals, an increased opiatergic tone is present with respect to androgen secretion. They postulated that this partly controls thl? hypersecretion of DHEA in this syndrome. However, the increased opiatergic tone rather seems to be a result of the hypersecretion of DHEA than a causative factor in its pathogenesis. The third way in which opiates could influence PCOD is by the way of hyperinsulinemia. Opioid peptides are involved in the regulation of insulin secretion, having a stimulatory effect in normal women". Laatikainen" studied the effect olan acute i.v. bolus ofnaloxone on insulin, IGF-1 and the protein binding factor for IGF: IGFBP-1 in PCOD patients. h'aloxone appeared to have no effkct on insulin and IGF-1 levels but significantly reduced the IGFBP1 levels in non-obese PCOD patients. The IGFBP-1 levels were already low and remained low in obese PCOD patients. It may be that a decreased endogenous opiatergc tone would decrease IGFBP-1, thereby allowing more IGF-1 to be unbound, which night then lead to increased androgen production. As the opiatergic tone seems to be increased



rather than decreased, this too argues against the endogenous opioids being involved in the pathogenesis of PCOD. All these factors, however, are still wholly hypothetical.

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Catecholamines Catecholamines seem to play a minor role in the regulation of inappropriate gonadotropin secretion. As was the case with opiates, it was postulated that in PCOD dopaminergic tone might be decreased in the hypothalamus. Neither Barnes and c o - ~ o r k e r sby ~ ~infusing dopamine and metoclopramide, nor Rosen and L o ~ o by ~ ~administering , disulfiram, were able to show such a decreased dopaminergc activity. Paradisi and c o - ~ o r k e r sexamined ~~ the influence of norepinephrine on pulsatile LH secretion by infusing thymoxamin (an a-adrenoceptor antagonist). They only showed an increase in pulse amplitude but pulse frequency did not change. This suggests that in PCOD women LHRH secretion is suppressed by central noradrenergc pathways. Unfortunately, no data are available on such an action in normally cycling women. LHRH agonists Several authors have carefully studied the effects of LHRH analogs on LH and FSH secretion. By rendering patients with PCOD hypogonadotropic and then discontinuing the analog treatment, they hoped to learn more about the pathogenesis of the disease by carefully studying the redevelopment of the syndrome. Two of these studies, one by Calogero and colleagues4hand one by de Ziegler and colleagues4’are typical examples of these. Calogero and c o - ~ o r k e r sshowed ~~ that, after an initial increase of immunoreactive (iLH) and biologically active LH (bLH), all hormones of the ovarian axis such as iLH, bLH, iFSH, testosterone, androstenedione, estrone and estradiol decreased. The bio LH/FSH ratio, which was around 8 before the beginning of treatment, decreased to about 4 on day 28, remaining at the same level for the duration oftreatment (56days).This ratio, according to the authors, is still elevated and therefore they claim that, even under analog treatment, the increased LH/FSH ratio remains present, albeit at a lower level. They conclude that this hallmark of the abnormality thus is independent of the secretion rates of the gonadotropins. During suppression no change was seen in the levels of DHEA-sulfate and cortisol. Both article^^^,^' agree as to the pattern ofrestoration ofthe origmal hormone levels after discontinuing analog treatment. The first hormone to recover is FSH which was its original level again 10 days after discontinuation. Estrone, estradiol, testosterone, androstenedione, iLH and bLH recovered at a much slower pace, only attaining their original levels approximately 6-7 weeks after discontinuation. This recovery pattern leads to a much better LH/FSH ratio in the first days of recovery. This, however, only sporadically leads to a spontaneous ovulation but it may well be the explanation why, at this time, it was much easier for

Filicori arid co-workerP to induce ovulation by pulsatile L H K H treatment. From theve results 110conclusions can be drawn with respect to the question posed origmally about the primary pathogenetic site of this disease.

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Pulsatile stimulation

If the inappropriate gonadotropin secretion in PCOD were the cause of the disturbances in thc rcgular menstrual pattern, then normalization of the LHRI-I sti~nulatorypattern would lead to regular ovulatory menstrual cycles. Lanibalk and colleagues'" showed that exogenous treatment with L H R H overrules the endogenous L H pulse pattern even i n w omen with hypergonadsotropic amenorrhea. Only when pulses were separated by at lcast 120 min were endogenously provoked pulses observed. Several authors have, using this principle, tried to induce ovulation in wonien with P C O D by iiiearls of pulsatilc L H R H stiIiiulation""i". Burger and co-workers" showed that indeed the LH secretory patterns fully follow exogenous LHKH stimulation and therefore completely normalize the gonadotropin stirnulatory pattern. Although they were able to obtain ovulation 74 times in 85 treatments in 11 w'onien, thr ovulations were so irregular that they finally concluded that, although pulsatile L H R H treatment changes the incidence of ovulatory cycles in PCOD, it does not really change the pathological mechanisms i n this disease" ' ' I . Therefore it is our beliefthat altered hypothalamic L H R H secretion is a result rather than the cause of this disease. Conclusion

Few arguments can be found for the hypothesis that an intrinsic abnormality of the central regulatory system of gonadotropin secretion in PCOS, or a factor acting through this system is responsible for the pathogenesis of this syndrome. Furthermorcs, the results of induction of ovulation by pulsatile L H R H adniinistration strongly argue for a pathogenetic factor other than inappropriate gonadotropin secretion. References





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Aieiiroendocrine coontrol in PCOS: Review


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Neuroendocrine control in polycystic ovary-like syndrome.

In this review article evidence is assembled from the neuroendocrinology of women with polycystic ovary-like syndrome (PCOS), to argue that the centra...
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