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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0581
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The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 8 3040-3043
Copyright © 2007 by The Endocrine Society

Ovarian Androgen Production in Postmenopausal Women

Robin H. Fogle, Frank Z. Stanczyk, Xiaohua Zhang and Richard J. Paulson

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Southern California, Keck School of Medicine, Los Angeles, California 90033

Address all correspondence and requests for reprints to: Robin H. Fogle, M.D., Women’s and Children’s Hospital, 1240 North Mission Road, Room 8K9, Los Angeles, California 90033. E-mail: robinfogle{at}yahoo.com.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Context: Several studies previously reported that the postmenopausal ovary produces androgens. However, these findings have recently been questioned in a group of women with adrenal insufficiency.

Objective: We sought to use contemporary assay methodologies to investigate whether the postmenopausal ovary is hormonally active and contributes to the circulating pool of androgens.

Design and Patients: Serum was collected from the ovarian veins of 13 postmenopausal women undergoing total abdominal hysterectomy and bilateral oophorectomy, with sufficient quantities obtained to allow for measurement of several hormones. Serum was also analyzed from peripheral blood collected preoperatively, intraoperatively, and postoperatively.

Setting: The study took place at the Los Angeles County Women’s and Children’s Hospital, University of Southern California Keck School of Medicine.

Main Outcome Measures: Testosterone (T), androstenedione (A), dehydroepiandrosterone (DHEA), estrone (E1), and estradiol (E2) were measured by RIA with preceding organic solvent extraction and Celite column chromatography.

Results: Statistically significant gradients were seen between the ovarian venous and peripheral samples for T, A, DHEA, E1, and E2. Postoperative levels of T and E1, but not A, DHEA, or E2, were statistically significantly lower than preoperative levels. A gradient for T between the ovarian venous and peripheral blood was present in four of five women who were menopausal for more than 10 yr.

Conclusions: The postmenopausal ovary is hormonally active, contributing significantly to the circulating pool of T. Furthermore, this contribution appears to persist in women as long as 10 yr beyond the menopause.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE POSTMENOPAUSAL OVARY has long been thought to be a significant source of circulating androgens, namely testosterone (T) and androstenedione (A). Judd et al. (1) were the first to demonstrate a decline in peripheral concentrations of T and A in postmenopausal women after bilateral oophorectomy. These investigators subsequently compared concentrations of T and A between the ovarian veins and peripheral circulation in postmenopausal women and were the first to observe concentration gradients of these androgens (2). Their findings were later supported by other reports (3, 4, 5, 6, 7, 8).

More recently, however, Couzinet et al. (9) challenged the role of the postmenopausal ovary in androgen production by evaluating T and A levels in postmenopausal women with adrenal insufficiency. Despite limitations in their study design, the authors presented strong evidence that the postmenopausal ovary does not contribute significantly to circulating androgen levels.

Our objective in the present study was to investigate, using improved ovarian venous sampling techniques and highly sensitive and specific RIA, the magnitude of androgen production by postmenopausal ovaries and to resolve the apparent discrepancies in the existing literature.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Thirteen postmenopausal women undergoing total abdominal hysterectomy and bilateral salpingooophorectomy for various indications were prospectively recruited. Table 1Go details the age, body mass index (BMI), preoperative serum FSH level, and surgical indication for each subject. The mean age (±SD) of the subjects was 57 ± 8 yr (range, 45–72 yr). Postmenopausal status was confirmed by preoperative FSH levels of more than 40 U/liter (mean ± SD, 50 ± 13 U/liter) and/or amenorrhea of more than 12 months (mean ± SD duration, 67 ± 47 months). The mean BMI (±SD) of the subjects was 32 ± 7 kg/m2 (range, 21–45 kg/m2). Patients were excluded from participation if they had poorly controlled diabetes, a history of hyperandrogenism, had recently used medications known to alter androgen production and/or metabolism such as cytochrome P450 modulators, or had any history of hormonal therapy within 6 wk of surgery.


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  		TABLE 1. Descriptive characteristics and surgical findings of postmenopausal women undergoing total abdominal hysterectomy and bilateral salpingooophorectomy

 
Protocol

Institutional Review Board approval and participant informed consent was obtained for this study. Peripheral blood samples were collected from participants preoperatively, either at the visit before or on the morning of surgery, as well as postoperatively (mean ± SD number of days after surgery, 55 ± 39 d). At the time of oophorectomy, blood was obtained from both the right and left ovarian veins using a technique that ensured adequate collection of blood (5–10 ml/side). After transection of the infundibulopelvic ligament, the clamp securing the medial aspect of the pedicle was released and the blood was collected in a sterile tube (Fig. 1Go). Simultaneously, an intraoperative peripheral blood sample was collected. All samples were allowed to clot and centrifuged, and the serum was stored at –20 C.


Figure 1
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  		FIG. 1. Sampling technique of ovarian venous effluent at the time of total abdominal hysterectomy and bilateral salpingooophorectomy.

 
Hormone assays

T, A, dehydroepiandrosterone (DHEA), estrone (E1), and estradiol (E2) were measured in all samples by RIA, after hexane:ethyl acetate (3:2) extraction and Celite column partition chromatography, as described previously (10, 11, 12). A, DHEA, and T were eluted in 0, 15, and 40% toluene in isooctane and E1 and E2 in 15 and 40% ethyl acetate in isooctane, respectively. The RIA for each analyte used an iodinated radioligand in conjunction with a highly specific antiserum. After a 16- to 18-h incubation period, a second antibody was used to separate antibody-bound from unbound steroid. The sensitivities of the T, A, DHEA, E1, and E2 RIAs were 2 ng/dl, 0.035 ng/ml, 0.04 ng/ml, 5 pg/ml, and 4 pg/ml, respectively. The intraassay and interassay coefficients of variation ranged from 6–9 and 12–14%, respectively, at low, medium, and high levels of the five different steroid hormones in quality control samples.

Statistical analysis

Comparisons of ovarian venous vs. intraoperative peripheral samples and of preoperative vs. postoperative samples were made using the Wilcoxon signed-rank test. Correlations were performed using the Spearman correlation test. Differences were considered statistically significant if P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The ovarian venous samples contained statistically significantly higher levels of T, A, DHEA, E1, and E2 than found in the peripheral circulation (P < 0.05) (Table 2Go). No statistically significant differences in the ovarian venous hormone concentrations from the right and left ovarian veins were seen, and the averaged values were used for analysis. Hormone concentrations between ovarian venous and intraoperative peripheral samples ranged from a 24-fold difference for T down to a 2-fold difference for DHEA.


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  		TABLE 2. Mean (range) concentrations of T, A, DHEA, E1, and E2 from ovarian venous and intraoperative peripheral serum

 
Postoperative serum levels of T and E1, but not of A, DHEA, or E2, decreased significantly compared with preoperative levels (P < 0.05) (Table 3Go). Despite the statistically significant difference between ovarian venous and peripheral serum concentrations for all of the hormones studied, the significant postoperative decline seen only in T and E1 emphasizes the existence of multiple factors regulating circulating steroid hormone concentrations.


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  		TABLE 3. Mean (range) concentrations of T, A, DHEA, E1, and E2 from preoperative and postoperative serum

 
In four of the five patients with more than 10 yr of amenorrhea (mean ± SD, 64 ± 8 yr of age), gradients between ovarian venous and intraoperative peripheral T levels were still present (Table 4Go). However, neither a correlation between age and preoperative T levels nor one between the duration of menopause and preoperative T levels was seen. Additionally, we found no correlation between age and preoperative A or DHEA levels.


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  		TABLE 4. Ovarian venous and intraoperative peripheral concentrations of T in subjects 10 or more years menopausal

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Several early studies demonstrated that the postmenopausal ovary is a source of androgens and, to a lesser extent, estrogens (1, 2, 3, 4, 5, 6, 7, 8). A weakness of these studies, as noted by some of the authors themselves, included suboptimal techniques for collecting ovarian venous blood, occasionally resulting in inadequate amounts of serum for analysis. Additionally, the use of assays less sensitive than those currently available is another limiting factor of these early studies. Even so, the demonstrations of androgen production by the postmenopausal ovary were convincing. However, these findings were recently questioned as the result of a study evaluating the ovarian contribution of T and A in a group of postmenopausal women with Addison’s disease (9). Using improved sampling techniques and contemporary assay methodologies, we sought to demonstrate that the postmenopausal ovary is hormonally active and to substantiate findings from previous studies that first established the postmenopausal ovary as a source of androgen production.

By demonstrating statistically significant gradients between ovarian venous and peripheral levels of T, A, and DHEA, along with a statistically significant decline in postoperative values of T after oophorectomy, we have confirmed that the postmenopausal ovary secretes androgens. Specifically, we found 24-fold and 4-fold higher concentrations of T and A, respectively, in the ovarian venous vs. peripheral circulation (Table 2Go) and decreases in T of 42% from the preoperative to postoperative time period (Table 3Go). A nonsignificant 17% decrease in postoperative A levels was observed. This relative lack of change is possibly attributable to postoperative compensatory production by the adrenal gland. DHEA demonstrated a 2-fold difference between the ovarian venous and peripheral serum, although a nonsignificant decline of only 18% was seen in postoperative DHEA levels. The lack of statistical significance could also be attributed to a type II error.

Of note, nine of our subjects were obese, a condition known to alter SHBG and other binding globulin concentrations. However, given the relatively short duration of the study and the fact that each patient served as her own control, the presence of obesity is unlikely to alter our overall conclusions. Furthermore, no correlations between BMI and the various steroid concentrations were detected (data not shown).

Given our results, we approximate that the postmenopausal ovary secretes 25 µg/d of T (bilateral production, ~50 µg/d). This is based on a gradient for T between the ovarian venous and peripheral serum of 6.9 ng/ml. Given that approximately 5 ml blood was collected from the ovarian vein over 2 min, we calculated an ovarian production rate of T of 1.04 µg/h. Our findings are comparable to the calculated ovarian contribution of 37 µg/d reported by Aiman et al. (5) and 60 µg/d reported by Adashi (13). Using similar calculations, we determined that the postmenopausal ovary directly contributes 11.5 µg/d of A (bilateral production ~ 23 µg/day) to circulating concentrations, an amount less than the 46 µg/d suggested by Aiman et al. (5) and the 300 µg/d suggested by Adashi (13).

Our findings support those of previous studies in which significant gradients between ovarian venous and peripheral concentrations, as well as between preoperative and postoperative concentrations, were demonstrated (1, 2, 3, 4, 5, 6, 7, 8). However, other studies have suggested limited steroid production by the postmenopausal ovary (9, 14). Couzinet et al. (9) compared postmenopausal women with adrenal insufficiency to women having had bilateral oophorectomy. They found that levels of T and A were undetectable in subjects with adrenal insufficiency despite having intact ovaries. The authors concluded that the adrenal gland, not the ovary, is responsible for postmenopausal androgen production. The study design was confounded, however, in that subjects with adrenal insufficiency were taking glucocorticoids, therapy that has previously been shown to alter ovarian steroid production (15).

In vitro data evaluating the presence of steroidogenic enzymes in the postmenopausal ovary exist, both supporting and refuting the possibility of continued androgen production (16, 17). Most recently, Havelock et al. (16) demonstrated the presence of all enzymes necessary for steroid production in postmenopausal ovarian stroma. The authors noted that previous contradictory findings may have resulted from the well-known heterogeneous distribution of secondary interstitial cells in the stroma or from phenotypic transformation of in vitro cultured stromal cells.

Our findings also substantiate postmenopausal ovarian production of both E1 and E2. A 3-fold difference for E1 and 7-fold difference for E2 were seen between the ovarian venous and peripheral hormone concentrations (Table 2Go). Despite this evidence of ovarian production, only postoperative E1 values declined significantly with a mean decrease of 26% (Table 3Go). A nonsignificant decline of 8% was seen in postoperative E2 levels. This lack of statistical significance for E2 may be the result of a small sample size. Additionally, it could be due to compensatory peripheral conversion of androgens to estrogens, although one would expect to see a nonsignificant decline in postoperative E1 levels as well if such were the case. This finding further underscores the influence of multiple factors involved in the regulation of peripheral steroid hormone concentrations.

Judd et al. (2) showed a 2-fold difference between the ovarian venous and peripheral circulation for both E1 and E2, whereas Aiman et al. (5) demonstrated a 1.4-fold and 4-fold difference between the ovarian venous and peripheral circulation for E1 and E2, respectively. In vitro data from Dennefors et al. (18) demonstrated E2 production from hilus strips of postmenopausal ovaries, providing additional evidence to the biological plausibility of estrogen production by the postmenopausal ovary.

In four of our five subjects who were postmenopausal for 10 or more years, a gradient for T between the ovarian venous and peripheral circulation was still present (Table 3Go). Results from the Rancho Bernardo Study demonstrating higher concentrations of total T in older postmenopausal women compared with younger postmenopausal women support the idea of hormonally active ovaries years beyond the menopause (8). Similarly, Davison et al. (19) demonstrated that the higher T levels seen in women with ovaries vs. those without ovaries persisted beyond 65 yr of age. Thus, our findings, along with those of others, support the idea that not only is the postmenopausal ovary still active in androgen production but also that this production seems to persist even into the late menopause.

In conclusion, using improved sampling techniques and contemporary, highly sensitive and specific RIA methodology, we have demonstrated production of androgens and estrogens by the postmenopausal ovary. Furthermore, we have shown that the ovarian contribution of androgens is sufficient to result in significant decreases in postoperative concentrations of T after bilateral oophorectomy. Lastly, we have demonstrated that this ovarian production of androgens appears to persist even 10 yr beyond the onset of menopause. We conclude that the postmenopausal ovary remains hormonally active, secreting significant amounts of androgens and estrogens. Given recent findings that ovarian preservation is beneficial to the overall health and longevity of postmenopausal women (20) and that oophorectomy before the age of 45 may actually be detrimental (21), we suggest that ovarian preservation be considered in appropriately selected women who may benefit from the effects of endogenous hormone production.


   Footnotes
 
Disclosure Statement: All authors have nothing to disclose.

First Published Online May 22, 2007

Abbreviations: A, Androstenedione; BMI, body mass index; E1, estrone; E2, estradiol; T, testosterone.

Received March 14, 2007.

Accepted May 11, 2007.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Judd HL, Lucas WE, Yen SSC 1974 Effect of oophorectomy on circulating testosterone and androstenedione levels in patients with endometrial cancer. Am J Obstet Gynecol 118:793–798[Medline]
  2. Judd HL, Judd GE, Lucas WE, Yen SS 1974 Endocrine function of the postmenopausal ovary: concentration of androgens and estrogens in ovarian and peripheral vein blood. J Clin Endocrinol Metab 39:1020–1024[Abstract/Free Full Text]
  3. Greenblatt RB, Colle ML, Mahesh VB 1976 Ovarian and adrenal steroid production in the postmenopausal women. Obstet Gynecol 47:383–387[Medline]
  4. Lucisano A, Acampora MG, Russo N, Maniccia E, Montemurro A, Dell’Acqu S 1984 Ovarian and peripheral plasma levels of progestogens, androgens and oestrogens in post-menopausal women. Maturitas 6:45–53[CrossRef][Medline]
  5. Aiman J, Forney JP, Parker CR 1986 Secretion of androgens and estrogens by normal and neoplastic ovaries in postmenopausal women. Obstet Gynecol 68:1–5[Medline]
  6. Nagamani M, Hannigan EV, Dillard EA, Dinh TV 1986 Ovarian steroid secretion in postmenopausal women with and without endometrial cancer. J Clin Endocrinol Metab 62:508–512[Abstract/Free Full Text]
  7. Sluijmer AV, Heineman MS, De Jong FH, Evers JLH 1995 Endocrine activity of the postmenopausal ovary: the effects of pituitary down-regulation and oophorectomy. J Clin Endocrinol Metab 80:2163–2167[Abstract]
  8. Laughlin GA, Barrett-Connor E, Kritz-Silverstein D, von Muhlen D 2000 Hysterectomy, oophorectomy, and endogenous sex hormone levels in older women: The Rancho Bernardo Study. J Clin Endocrinol Metab 85:645–651[Abstract/Free Full Text]
  9. Couzinet B, Meduri G, Lecce MG, Young J, Brailly S, Loosfelt H, Milgrom E, Schaison G 2001 The postmenopausal ovary is not a major androgen-producing gland. J Clin Endocrinol Metab 86:5060–5066[Abstract/Free Full Text]
  10. Goebelsmann U, Bernstein GS, Gale JA, Kletzky OA, Nakamura RM, coulson AH, Korelitz JJ 1979 Serum gonadotropin testosterone estradiol and estrone levels prior to and following bilateral vasectomy. In: Lepow IH, Crozier R, eds. Vasectomy: immunologic and pathophysiologic effects in animals and man. New York: Academic Press; 165–181
  11. Goebelsmann U, Horton R, Mestman JH, Arce JJ, Nagata Y, Nakamura RM, Thorneycroft IH, Mishell Jr DR 1973 Male pseudohermaphroditism due to testicular 17-hydroxysteroid dehydrogenase deficiency. J Clin Endocrinol Metab 36:867–879[Abstract/Free Full Text]
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  14. Abraham GE, Lobotsky J, Lloyd CW 1969 Metabolism of testosterone and androstenedione in normal and ovariectomized women. J Clin Invest 48:696–703[Medline]
  15. Cortes-Gallegos V, Gallegos AJ, Tovar NB, Cervantes C, Parra A 1975 Effect of paramethasone acetate on ovarian steroids and gonadotropins. I. Normal menstrual cycle. J Clin Enocrinol Metab 41:215–220[Abstract/Free Full Text]
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