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BRIEF REPORT |
Division of Reproductive Endocrinology and Infertility, College of Physicians & Surgeons, Columbia University, New York, New York 10032
Address all correspondence and requests for reprints to: Jeff G. Wang, Department of Obstetrics and Gynecology, Columbia University, 622 W 168th Street PH-16, New York, New York 10032. E-mail: jw781{at}columbia.edu.
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Abstract |
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Methods: Baseline and dynamic endocrine profiles during controlled ovarian hyperstimulation for women with HA/PCOM [n = 6, median (interquartile range) age 30 yr (28–31), body mass index (BMI) 19.2 kg/m2 (18.0–19.2)] were retrospectively compared with those of women with PCOS [n = 10, age 33 (31–34), BMI 24.8 (23.2–27.6)] and normoovulatory controls [n = 20, age 33 (31–35), BMI 21.5(20.3–23.1)]. Long-term outcomes for five women with HA/PCOM were followed during their spontaneous recovery from HA.
Results: With the exception of decreased LH [0.7 (0.3–0.8) vs. 6.0 IU/liter (4.8–7.4); P = 0.003], FSH [3.9 (2.5–5.7) vs. 7.5 IU/liter (5.3–9.5); P < 0.025], and estradiol [20 (14–24) vs. 32 pg/ml (20–39); P < 0.027], baseline endocrine profiles of women with HA/PCOM did not differ significantly from those of normoovulatory controls in terms of 17
-hydroxyprogesterone, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androstenedione, and total testosterone. However, controlled ovarian hyperstimulation with similar doses of gonadotropins resulted in an excess of androgen production compared with the controls [
androstenedione per dominant follicle 0.30 (0.23–0.37) vs. 0.10 ng/ml (0.05–0.18), P = 0.005; testosterone per dominant follicle 16 (7–24) vs. 6 ng/dl (2–12), P = 0.04], and these levels were comparable to those of women with PCOS. Recovery from HA/PCOM in some patients was associated with the development of oligomenorrhea and symptoms of androgen excess.
Conclusions: Women with HA/PCOM may have inherently hyperandrogenic ovaries but are quiescent due to low gonadotropins from the hypothalamic inactivity. The exaggerated ovarian androgen response to low-dose gonadotropin stimulation in these women is consistent with the clinical observation that hyperandrogenism emerges in association with weight gain and the recovery of hypothalamic function. Over time, these patients may fluctuate between symptoms of HA and PCOS, depending on the current status of hypothalamic activity. The fluidity of this transition in HA/PCOM challenges the simple dichotomous definition of PCOS using the Rotterdam criteria, which categorizes the two conditions as being mutually exclusive.
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Introduction |
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The smattering of data on ovarian morphology in HA has described the ovaries as being multifollicular but without the increased stromal area characteristic of what has been referred to as polycystic ovarian morphology (PCOM) (2). In a study using pelvic ultrasound to assess the ovarian morphology of 31 women with HA, the ovarian dimensions were significantly smaller than those of normoovulatory controls, and the morphology was not polycystic (3).
Albeit infrequent, we have encountered classical PCOM as defined by the Rotterdam criteria (at least one ovary greater than 10 cm3, at least 12 peripheral cysts between 2 and 9 mm) as well as with increased ovarian stroma in the evaluation of patients with HA (HA/PCOM). In the absence of hyperandrogenism or hyperandrogenemia, these patients clearly do not meet the diagnostic criteria for polycystic ovary syndrome (PCOS) set forth by the National Institutes of Health conference in 1989 (4).
Although the 2003 Rotterdam criteria for PCOS broadened the definition to include those women with irregular cycles and PCOM even in the absence of androgen excess, the diagnosis can only be made in the absence of another disorder such as HA (5). However, both HA and PCOS are diagnoses of exclusion, and which condition should supersede the other in cases of HA/PCOM poses an interesting dilemma. In a series characterizing a cohort of women with HA in conjunction with PCOM, it was reported that their ovarian response to gonadotropin stimulation was similar to those of patients with PCOS and significantly greater than that of women with HA without PCOM (6).
In this paper we hypothesize that HA and PCOS may coexist, and the ovarian hyperandrogenism in HA/PCOM may be masked by the suppressed hypothalamic-pituitary axis. We aim to explore this hypothesis by using a retrospectively identified cohort of 11 women who presented with HA/PCOM. Six of these women with persistent HA underwent controlled ovarian hyperstimulation (COH) and were assessed if their ovarian androgen response to gonadotropins may be enhanced as occurs in women with classical PCOS. The remaining five women spontaneously recovered from HA and were observed clinically to determine if symptoms of PCOS ensued.
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Subjects and Methods |
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During the period of 2001–2006, we encountered 11 women, ages between 21 and 35 yr, who presented with amenorrhea and were subsequently diagnosed with HA after undergoing complete physical, laboratory, and imaging studies to exclude other potential causes (Table 1
). These 11 subjects also had the classical appearance of bilateral PCOM on transvaginal ultrasound but had no clinical or biochemical evidence of hyperandrogenism.
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There were 10 age-matched women with infertility and PCOS diagnosed by oligomenorrhea, clinical or biochemical evidence of hyperandrogenism, and PCOM included for comparison. The control group consisted of 20 age-matched normoovulatory subjects with infertility, who had normal ovarian morphology and the absence of hyperandrogenism or hyperandrogenemia. This study was approved by the Institutional Review Board of the Columbia University.
Protocol
The women who wished to conceive underwent comprehensive evaluations and were deemed suitable candidates for COH with either intrauterine insemination (IUI) or timed intercourse. Daily sc injection with Gonal-F (Serono Inc., Rockland, MA) was initiated on an arbitrary date in subjects with HA but on the second day of spontaneous menses or after progestin induced bleeding in the normal controls and women with PCOS. An initial dosage of 150 IU/d recombinant human FSH was used, and the dosage was modified when there was an increased risk for ovarian hyperstimulation. The number of ovarian follicles and their dimensions were measured by transvaginal ultrasound (LOGIQ, 6.5 MHz; General Electric Co., Fairfield, CT), and serum estradiol (E2) assays were used in conjunction to monitor ovarian responses. Recombinant choriogonadotropin , Ovidrel (Serono Inc.), was administered when at least one follicle with a mean diameter greater than 17 mm was detected. IUIs or timed intercourse was performed 36 h after the administration of human chorionic gonadotropin.
Assays
Basal hormone levels were determined randomly on patients with HA and on d 2–3 spontaneous or progestin-induced menses in normoovulatory controls or women with PCOS. Serum levels of FSH, LH, E2, and testosterone (T) were measured by chemiluminescence using Immulite 2000 (Siemens Corp., New York, NY). 17-hydroxyprogesterone (17-OHP) and dehydroepiandrosterone (DHEA) were quantified using commercially available RIA kits (Siemens), and androstenedione and DHEA-sulfate (DHEA-S) by ELISA (Siemens). The intraassay coefficient of variation for the aforementioned assays ranged from 2.3–9.6%, and the interassay coefficient of variation ranged from 6.4–15.6%.
Statistical analyses were performed using nonparametric tests including the Mann-Whitney U test and Wilcoxon signed ranks test as appropriate. Results are expressed as median ± interquartile range. A P value less than 0.05 was considered statistically significant. Data were analyzed by Statistical Package for the Social Sciences (SPSS version 11.5; SPSS, Inc., Chicago, IL).
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Results |
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). Median body mass index (BMI) was higher in patients in PCOS and lower in patients with HA/PCOM compared with that of normoovulatory controls (P < 0.001). Baseline median LH and E2 in HA/PCOM were significantly lower than those of the other groups (P < 0.003 and P < 0.027, respectively).
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). However, median total T was significantly higher among women with PCOS (P < 0.04) compared with the other two groups. In addition, androstenedione to DHEA and T to DHEA ratios were significantly higher in women with PCOS than in HA/PCOM and in the controls (P < 0.001).
During COH, all three groups received similar dosages of total gonadotropin that resulted in the development of similar numbers of large follicles greater than or equal to18 mm (Table 2). The number of intermediate follicles between 12 and 15 mm was greater in women with PCOS (P < 0.05). The increase in androstenedione after gonadotropin stimulation, whether adjusted by the number of dominant follicles more than or equal to 18 mm or the dynamics of E2 increase (E2), was significantly higher in HA/PCOM and in PCOS when compared with that of normoovulatory women (P < 0.005 and P < 0.013, respectively).
Similarly, the magnitude of total T increase (T) during COH adjusted for follicular development was significantly greater in women with HA/PCOM and in PCOS compared with the normoovulatory controls (P < 0.04). When adjusted by E2, T in women with HA/PCOM remained significantly greater than that of normoovulatory controls (P < 0.02).
The uncontrolled follow-up of the five subjects with HA/PCOM who did not undergo COH ranged from 1–3 yr. All subjects experienced increases in BMI during this time, ranging from 5–18%. All five women developed oligomenorrhea during follow-up, whereas three of them developed evidence of hyperandrogenism.
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Discussion |
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Women with PCOS had the highest T compared with the other two groups at baseline. Furthermore, the higher ratios of androstenedione to DHEA and T to DHEA in this group suggest an increased enzymatic activity involved in the biosynthesis of androgens from DHEA compared with women with HA/PCOM and controls. The quiescence of the hypothalamic-pituitary-ovarian axis in women with HA/PCOM most likely explains their normal baseline androgen status.
The secretion of androstenedione and T per dominant follicle (
18 mm) in women with HA/PCOM and in PCOS as a result of COH was significantly higher than that of the normoovulatory group. When normalized by E2, the dynamics of androstenedione and T during COH in women with HA/PCOM were still greater than that of the normoovulatory controls. Therefore, despite PCOM in women with HA not being associated with elevated androgen levels at baseline, it appears to be associated with increased androgen secretion when stimulated by gonadotropins.
The occurrence of PCOM in HA is likely independent of extraovarian influences. Hypothalamic pulsatility is disrupted as evidenced by the low LH levels. Although insulin sensitivity could not be assessed due to the retrospective nature of this study, an investigation comparing normoovulatory controls to a HA population similar to ours in terms of age and BMI showed that HA is associated with subnormal levels of fasting insulin with increased insulin sensitivity (7). Thus, hyperinsulinemia is unlikely to contribute to intraovarian hyperandrogenism and the PCOM in HA. Therefore, alterations in the endogenous ovarian androgen biosynthesis such as an increase in the ovarian cytochrome P450c17 activity found in some women with PCOS (8, 9) may contribute to the ovarian morphology. Under gonadotropin stimulation, inherent enzymatic overactivity may result in the exaggerated androgen production observed in these women with HA (10).
In the uncontrolled follow-up of the five women in this cohort, HA spontaneously recovered (Table 1). In these women over several years, a clinical picture resembling that of PCOS emerged with irregular cycles and some symptoms of hyperandrogenism. These clinical observations are consistent with our data from the analysis of androgen dynamics during COH, suggesting the possibility that the ovaries in women with HA/PCOM may be inherently hyperandrogenic but are quiescent due to low gonadotropins from the hypothalamic inactivity. In this state these women are hypoestrogenic and should be managed as other women who have HA. At later stages they may exhibit more characteristic features of PCOS depending on the status of their hypothalamic function.
This entity HA/PCOM, therefore, may challenge the definition of PCOS using the Rotterdam criteria as this may be a transitional state between women who would be normally excluded from the diagnosis by having HA. Nevertheless, at a later time, these same women may develop a more characteristic picture of PCOS. However, from a clinical perspective, it is probably most appropriate to treat women with HA/PCOM based on their current hypothalamic and estrogenic status, with the awareness that this status may change with time.
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Footnotes |
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First Published Online January 29, 2008
Abbreviations: BMI, Body mass index; COH, controlled ovarian hyperstimulation; DHEA, dehydroepiandrosterone; DHEA-S, DHEA-sulfate; E2, estradiol; 17-OHP, 17-hydroxyprogesterone; HA, hypothalamic amenorrhea; IUI, intrauterine insemination; PCOM, polycystic ovarian morphology; PCOS, polycystic ovary syndrome; T, testosterone.
Received August 1, 2007.
Accepted January 18, 2008.
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References |
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activity and serum free testosterone after reduction of insulin secretion in polycystic ovary syndrome. N Engl J Med 335:617–623-hydroxylase messenger ribonucleic acid stability in theca cells isolated from women with polycystic ovary syndrome. J Clin Endocrinol Metab 90:1720–1727
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