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From: Contemporary Endocrinology: Androgen Excess Disorders in Women:
Polycystic Ovary Syndrome and Other Disorders, Second Edition Edited by: R. Azziz et al. © Humana Press Inc., Totowa, NJ
17
Hypothalamic–Pituitary–Gonadotropic Dysfunction in the Polycystic Ovary Syndrome
R. Jeffrey Chang and Rinku V. Mehta
SUMMARY
Almost all women with the polycystic ovary syndrome exhibit increased luteinizing-hormone (LH) secre- tion and decreased levels of serum follicle-stimulating hormone. By inference, hypothalamic gonadotropin- releasing hormone (GnRH) activity is increased, although other factors appear to affect the relationship between GnRH and LH interaction. The precise mechanism(s) responsible for inappropriate gonadotropin release are not known, but they appear to involve the effects of abnormal ovarian steroidogenesis, including androgen excess.
Other factors may include abnormal insulin secretion and possibly extrahypothalamic neurotransmitters.
Key Words: Gonadotropin-releasing hormone; GnRH; luteinizing hormone; LH; follicle-stimulating hor- mone; FSH; androgen; estrogen; insulin.
1. INTRODUCTION
Gonadotropic abnormalities in the polycystic ovary syndrome (PCOS), mainly elevated luteiniz- ing hormone (LH) levels, were reported as early as 1958 using urinary bioassays. Subsequently, radioimmunoassays were developed that allowed the detection and measurement of circulating gona- dotropins, suggesting that a significant fraction of women with PCOS had an elevated (>2–3) LH–to–
follicle-stimulating hormone (FSH) ratio. Following, we review our current understanding of the prevalence, mechanism, and role of gonadotropic abnormalities in PCOS.
2. BACKGROUND
Women with PCOS are distinctive with respect to reproductive neuroendocrine function charac- terized by elevated 24-hour mean serum LH concentrations, greater LH responses to gonadotropin- releasing hormone (GnRH), and increased LH pulse frequency and amplitude compared to those found in normal women (1). The mechanism(s) responsible for this increased release of LH are not well understood. A particular characteristic of LH secretion in PCOS is increased pulse frequency, the periodicity of which is approximately 1 hour. This rapid rate of LH release does not appear to be altered by experimental manipulation under physiological conditions (2,3). Previous in vivo studies in animals have demonstrated that individual LH pulses are correlated to isolated bursts of endog- enous GnRH release (4). Correspondingly, these observations imply that in PCOS the episodic pat- tern of pituitary LH secretion reflects a parallel increase in hypothalamic GnRH activity.
In PCOS the relationship between GnRH pulse frequency and gonadotrope responsiveness may be
a primary mechanism underlying inappropriate gonadotropin secretion. First, previous studies in rodents
have demonstrated a preference for the expression of the gene for the E-subunit of LH (LHE) in response
to rapid rates of GnRH delivery, whereas E-subunit of FSH (FSHE expression is suppressed (5).
Second, not only does GnRH drive LH release, it has been shown in normal women to self-prime the pituitary and thereby contributes to the increased LH sensitivity to subsequent GnRH stimulation (6).
Collectively, these findings suggest that the profound abnormality of gonadotropin secretion in PCOS may be a primary consequence of increased hypothalamic GnRH activity.
2.1. GnRH in PCOS
In humans it has been shown that administration of intravenous GnRH at varying frequencies may dictate the rate of LH release as well as alter basal concentrations (7,8). In hypogonadotropic hypogonadal individuals, an increase in the rate of GnRH administration from every 90 minutes to every 60 minutes was not associated with corresponding increases in serum LH or changes in pulse amplitude, whereas increasing GnRH frequency to 30-minute intervals resulted in elevated LH levels and reduction of pulse amplitude (7). When the rate of GnRH administration was increased to every 15 minutes, both the concentration and amplitude of LH release were markedly diminished as a result of receptor desensitization. Thus, although consistent with the primacy of increased hypothalamic GnRH, an LH pulse frequency of 1 hour may represent a physiological limit beyond which more frequent pulses in women do not occur.
In normal ovulatory women during the late follicular phase and at midcycle, as well as in post- menopausal women, it has been documented that LH pulse frequency approximates 60 minutes (9).
In addition, previous studies have shown that the GnRH release from the medial basal hypothalamus of the fetus and adult has a periodicity of about 1 hour (10). These findings suggest that in PCOS women, the pulse frequency and, to some degree, magnitude of gonadotropin secretion are estab- lished by hypothalamic GnRH activity. However, beyond the essential role of GnRH, LH responsive- ness to GnRH and, accordingly, maximal increases in LH pulse amplitude are probably influenced by other factors.
2.2. Role of Estrogen and Progesterone
It has been suggested that the positive feedback effects of chronic estrogen secretion associated with this disorder may bring about an increase of LH either by a direct effect on gonadotrope sensitiv- ity to GnRH or indirectly by facilitating GnRH pulse frequency. In vitro, estrogen has been shown to increase the fraction of individual gonadotropes responding to GnRH that is consistent with amplifi- cation of LH responses to GnRH in normal women receiving estradiol benzoate (11). In PCOS, baseline levels of estrone and estradiol have been correlated with LH responses to GnRH (1). How- ever, prolonged administration of estrone to PCOS patients failed to raise circulating levels of LH beyond baseline values or increase GnRH-stimulated LH responses (12). In animals it has been dem- onstrated that estrogen enhances GnRH pulse frequency, and in women with PCOS, serum GnRH levels are increased. That estrogen may exert an effect at the hypothalamus in PCOS is supported by the strong positive correlation of mean serum estradiol levels to GnRH pulse frequency (13). Despite these findings, the capacity of exogenous estrogen, administered at physiological levels, to alter LH pulse frequency has not been demonstrated.
In contrast to estrogen, progesterone, either alone or in combination with estrogen (oral contracep-
tive), was shown to suppress circulating LH levels and LH pulse frequency in both PCOS and normal
women (14). The observation that suppression of LH release was more pronounced in normal women
than women with PCOS suggested to the investigators that increased LH pulse frequency might
reflect a fundamental property of the hypothalamic pulse generator in PCOS. Moreover, in a study of
women with PCOS that employed the administration of progesterone and estradiol at physiological
concentrations equivalent to those found in the midluteal phase of normal women, LH pulse fre-
quency was not diminished compared to the reduced rate found in a group of normal women studied
similarly (15).
2.3. Role of Androgens
As the outstanding abnormality of ovarian steroid production in PCOS, hyperandrogenemia has been implicated as a potential cause of increased LH secretion. In vitro, it has been shown that andro- gen administration increased hypothalamic GnRH pulse generator activity in rodents. Examination of LH secretion in hyperandrogenic patients with congenital adrenal hyperplasia revealed that mean LH levels and LH responses to GnRH were increased, which tended to normalize with the onset of treatment and corresponding lowered androgen levels (16). By comparison, other studies have not been able to detect an increase in LH following the administration of androgen. Short-term infusion of androgen to both normal women and women with PCOS failed to alter basal LH secretion (17). In addition, high-dose androgen infusion in normal women appeared to result in an acute reduction of serum LH levels (18).
Notwithstanding these past findings, recent studies have indicated that excess androgen produc- tion may have a significant influence on LH pulse frequency in women with this disorder. In PCOS women pretreated with an androgen-blocking agent, administration of estrogen and progesterone at physiological concentrations was associated with a reduction of LH pulse frequency comparable to that observed in normal women treated similarly (19). These findings suggested that in PCOS, high circulating levels of androgen prevent the negative feedback effects of estrogen and progesterone on LH pulse release, as noted in earlier studies. Moreover, the physiological relevance in women relates to a rapid rate of spontaneous hypothalamic GnRH activity, which is regulated by the feedback effects of ovarian steroids.
2.4. Role of Insulin
Insulin has also been implicated as a potential regulator of LH secretion in PCOS. The notion that insulin may contribute to inappropriate gonadotropin secretion in PCOS has been largely based on in vitro studies, which demonstrated that rat pituitary cells preincubated with insulin exhibited increased LH responsiveness following administration of GnRH in a dose-dependent manner compared to un- treated cells (20). Interestingly, an effect of insulin was not observed when these studies were per- formed in the presence of serum-supplemented media. Efforts to determine an effect of insulin in PCOS women have not documented consistent alterations in LH secretion or LH release following GnRH stimulation. Reduction of hyperinsulinemia by administration of insulin-lowering drugs to PCOS patients or dietary restriction resulted in decreased mean serum levels of androgens and LH in some cases, whereas in others an accompanying decrease in LH was not found. Interestingly, the failure to document a decline in LH levels despite improved insulin sensitivity was independent of whether ovulatory activity had resumed in these studies.
Recently we have explored the role of insulin on gonadotropin secretion in PCOS and normal women. Using the hyperinsulinemic-euglycemic clamp technique, our results demonstrated that epi- sodic gonadotropin secretion and LH responses to multidose GnRH stimulation were not altered by insulin infusion over an interval of 12 hours in both groups (21). In particular, endogenous serum LH levels were unchanged prior to and immediately following initiation of the insulin clamp (Table 1).
In an extension of these studies, episodic LH secretion and LH responses to GnRH stimulation were not influenced by an insulin-lowering drug, pioglitazone, administered for 3 months (Fig. 1) (22).
These findings confirm and clarify previous studies, which have been unable to document consistent alterations in LH secretion or LH release following GnRH stimulation following insulin administra- tion in normal women and women with PCOS. In normal women undergoing long-term insulin administration by a 16-hour hyperinsulinemic-euglycemic clamp, mean serum LH levels, measured every hour, remained unchanged during the entire course of infusion (23).
During 6-hour insulin infusions randomized to either of 2 consecutive days in women with and
without PCOS, consistent alterations in mean serum LH, LH pulse frequency or pulse amplitude, and
LH release following GnRH could not be documented (24). Collectively, these results may explain
Table 1
Effect of Insulin Infusion on 12-Hour Composite Mean LH, Pulse Frequency, and LH Pulse Amplitude in Women With and Without PCOS
Normal (n = 9) PCOS (n = 11) 12-hour composite LH (mIU/mL)
No insulin 3.5 r 0.4 6.7 r 0.1a
Insulin infusion 3.2 r 0.3 4.9 r 0.9
LH pulse frequency (no./12 hours)
No insulin 8.8 r 0.8 10.2 r 0.4b
Insulin infusion 8.1 r 0.8 10.3 r 0.5b
LH pulse amplitude (mIU/mL)
No insulin 1.6 r 0.2 1.8 r 0.3
Insulin infusion 1.6 r 0.2 1.4 r 0.2
Meanr SE depicted.
Normal vs PCOS; ap < 0.01; bp < 0.006.
LH, luteinizing hormone; PCOS, polycystic ovary syndrome. (From ref. 21.)
Fig. 1. Time-course of mean (rSE) serum luteinizing hormone (LH) concentrations after intravenous admin- istration of three successive doses of gonadotropin-releasing hormone (GnRH) given at 4-hour intervals during the hyperinsulinemic-euglycemic clamp (80 mU/m2) in women with polycystic ovary syndrome (PCOS) before and after treatment with pioglitazone. No significant differences were detected in the percent increment of LH from baseline as a result of treatment. (From ref. 22.)
why changes in serum LH were not observed in women with PCOS treated with insulin-lowering drugs despite significant reductions in circulating androgen levels. Alternatively, interpretation of these clinical trials is potentially confounded by several factors. First, most of the patients studied were obese, and it has been shown that obesity is inversely correlated to LH secretion in PCOS.
Second, hyperinsulinemia is positively correlated with the body mass index (BMI) in women with
this syndrome. Third, the occurrence of ovulation in PCOS is associated with a lowering of LH levels
into the normal range. Although additional studies are necessary, the evidence to date has not clearly
demonstrated a functional interaction between insulin and LH in this disorder.
2.5. Role of Obesity
The inability of insulin to induce alterations in LH secretion in women with PCOS is relevant to studies that have shown that both 24-hour insulin levels and BMI are inversely correlated to serum LH and LH pulse amplitude (Fig. 2) (2,3). In an effort to address the relationship between body mass and LH secretion, obese women with PCOS were subjected to extreme caloric restriction over 7 days, during which a small but significant weight loss occurred. Daily LH secretion was increased, as evidenced by significantly greater LH levels and increased LH pulse amplitude, although changes in LH pulse frequency were not observed (25). Similar findings were reported in obese women with PCOS who were placed on very low-calorie intake for 6 weeks and lost 8% of their original weight.
Nocturnal LH secretion increased after weight loss compared with pretreatment values (26). These changes were accompanied by improved insulin sensitivity and glucose utilization that correlated with increased LH secretion. Whether the weight loss influenced gonadotropin secretion directly or indirectly through alterations of metabolic function induced by caloric restraint such as reduced insu- lin secretion or decreased availability of glucose for oxidation in the brain could not be determined.
Nevertheless, these results suggest that obesity may contribute to diminished LH pulse amplitude in women with PCOS compared with that observed in women without the syndrome.
2.6. Antiepileptic Drugs, Gonadotropic Abnormalities, and PCOS
Increased LH pulse frequency, as well as other features of PCOS, has been described in women with epileptic disorders or women treated with antiepileptic drugs (27,28). These observations have led to the intriguing consideration that epilepsy or treatment with antiepileptic drugs (sodium valproate in particular) and PCOS are causally related (see also Chapter 10). The link between epi- leptic and postseizure ictal states may involve stimulation of excitatory neurotransmitters, the recep- tors of which exist in hypothalamic nuclei that influence GnRH release. Thus, the consequences of epileptic activity may result in increased GnRH activity and simulate the pattern of increased LH secretion in PCOS. In addition to altered LH secretion, polycystic ovaries and hyperandrogenism have been reported in untreated and treated women with epileptic seizures, which strengthen the possible association between PCOS and epilepsy (28).
Fig. 2. Regression of body mass index (BMI) for polycystic ovary syndrome (PCOS) (䊉) and normal control (NC) (䊊) women against luteinizing hormone (LH) pulse frequency (PCOS and NC: p = NS); LH pulse ampli- tude: r = -0.63; p < 0.001; NC: p = NS), and 24-hr mean LH levels (PCOS: r = - 0.63; p < 0.001; NC: p = NS).
Values for LH pulse amplitude and 24-hour mean are log10 transformed. Shaded area represents 95% confi- dence interval for NC (frequency: 11–22 pulses/24 hours; amplitude: 2.6–9.2 IU/L; 24-hour mean: 6.1–8.2 IU/L).
(From ref. 2.)
A mechanistic role for antiepileptic medication, including sodium valproate, in the development of excess androgen production or follicle cyst formation in treated subjects has not been elucidated.
Unfortunately, the vast majority of reports linking epilepsy or antiepileptic medication to PCOS have been beset by poor experimental design and insufficient rigor to determine whether causality exists.
2.7. FSH Secretion in PCOS
In contrast to LH, FSH secretion in PCOS is decreased, as indicated by significantly lower serum concentrations compared with those found in normal women during the early follicular phase of the menstrual cycle (1). In addition, FSH responses to GnRH stimulation are reduced, as shown in some, but not all studies. The precise underlying basis for the decreased FSH secretion in PCOS has not been determined, although the negative-feedback effect of chronic unopposed estrogen secretion in these women has been implicated as a mechanism. Support for this concept has been demonstrated by a study in which women with were treated with estradiol benzoate for 2 weeks (12). Daily measure- ment of serum gonadotropin levels revealed a progressive decline of circulating FSH, whereas serum LH concentrations remained unaltered, resulting in a decrease in the LH:FSH ratio. The reduction in serum FSH may also reflect the activity of hypothalamic GnRH. As mentioned earlier, increased frequency of pulsatile GnRH predisposes to a preference for LHE gene expression at the expense of the FSHE gene (5).
3. SUMMARY/CONCLUSIONS
The characteristic neuroendocrine alterations in PCOS are increased LH secretion and decreased circulating FSH levels, which likely reflect increased activity of the hypothalamic GnRH pulse gen- erator. Increased GnRH release favors the gene expression of LHE and inhibits the expression of FSHE. Heightened GnRH release and inappropriate gonadotropin secretion may also reflect the influence of abnormal ovarian steroid production, including chronic estrogen secretion in the absence of progesterone and excess androgen production. In contrast to studies in animals, clinical studies in women with PCOS to date have not demonstrated a role for insulin on gonadotropin secretion in this disorder. A role for excitatory hypothalamic neurotransmitters in LH secretion has not been estab- lished, although the occurrence of PCOS symptomatology in women with epileptic disorders or women treated with antiepileptic drugs is provocative.
4. FUTURE AVENUES OF INVESTIGATION
Studies are needed to further establish which factors may be responsible for the mechanism of inappropriate gonadotropin section in PCOS, including steroid hormones, obesity, insulin, and possi- bly neurotransmitters. Moreover, the role of enhanced GnRH–LH interaction in the genesis of this disorder has not been clarified. That PCOS appears to be a heritable condition speaks to a genetic basis for the disruption of reproductive physiology, including the possibility of abnormal activity of the GnRH pulse generator.
KEY POINTS
• PCOS is a heterogeneous disorder in which the characteristic neuroendocrine abnormality is hypersecre- tion of LH and decreased circulating FSH.
• The precise etiology of the increased LH secretion is yet to be elucidated, but ovarian steroids and insulin appear to be involved.
• Recent studies have suggested that PCOS is a heritable condition; therefore, the abnormal functioning of the GnRH pulse generator may be genetically programmed.
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