Carmina, Enrico MD; Campagna, Anna Maria MD; Lobo, Roger A. MD
Polycystic ovary syndrome (PCOS) is a very common disorder that may have different presentations depending on the severity of various endocrine and metabolic alterations.1,2 In most studies, the more severe phenotypes (including chronic anovulation and hyperandrogenism) are more prevalent.
However, the mean age of the patients studied has generally been women in their 20s, and some studies have suggested that the clinical and biochemical presentation of PCOS might attenuate with aging. In PCOS, androgen levels may decrease before menopause,3–6 whereas polycystic ovarian morphology may become less common.7–9 It has also been reported that women with PCOS may attain more regular cycles with aging and that fertility potential may be prolonged because of their larger follicular cohort.10 However, aging may be associated with more severe metabolic alterations and in particular with a worsening of insulin resistance11 and changes in body composition favoring abdominal obesity.12
Therefore, because the endocrine and metabolic features of PCOS may vary with age, the relative prevalence of the different phenotypes as well as the presence of criteria allowing for the diagnosis of PCOS may be affected. Although some studies have reported follow-up of clinical and hormonal data of patients with characteristics suggestive of PCOS,13 these studies are different in that the clinical features were self-reported. Also, oligomenorrhea at 14 years of age as reported in one study13 cannot be considered diagnostic of PCOS.
We report a longitudinal study in a large group of women with PCOS. These women were evaluated during their early 20s and followed for 20 years. The focus of the study was not regarding fertility status or pregnancy, but rather the endocrine and metabolic changes that might occur with aging. Our data show that progressing from the second to the fourth decade of life is associated with a progressive reduction of androgen levels and a higher rate of ovulatory cycles. In many patients, the diagnosis of PCOS could no longer be made; and in others, the phenotype was less severe.
MATERIALS AND METHODS
Between 1985 and 1990, 314 women aged 20–25 years (mean age 21.7±1 year) with symptoms or signs of hyperandrogenism, oligomenorrhea, or both were evaluated. The patients were referred to the Endocrine Unit of the Department of Clinical Medicine of the University of Palermo because of symptoms of hyperandrogenism, oligomenorrhea, or both. At the time of their evaluation, all referred patients had not had treatment for at least 3 months. Thirty-five healthy control participants, aged 20–25 years, with normal body weight, normal ovulatory menses, and no clinical or biochemical signs of hyperandrogenism also were studied for comparisons of baseline hormonal data.
Clinical hyperandrogenism was defined by the presence of hirsutism. Hirsutism was assessed by Ferriman-Gallwey-Lorenzo scores with patients having scores 8 or greater being considered as hirsute.14 Biochemical hyperandrogenism was defined as finding elevated levels of serum androgens (total testosterone, dehydroepiandrosterone sulfate, or both). Oligomenorrhea was defined as menstrual cycle intervals 35 days or longer. In patients and control participants, the following data were assessed: age, menstrual status, scoring of clinical hyperandrogenism, body mass index (BMI, calculated as weight (kg)/[height (m)]2), waist circumference, serum levels of testosterone, dehydroepiandrosterone sulfate, 17-hydroxprogesterone, progesterone, insulin, blood glucose, and ovarian ultrasonography.
Serum androgens and 17-hydroxprogesterone were determined during the follicular phase (days 5–8) of spontaneous or progestin-induced cycles. Serum progesterone was determined on days 21–24 of the menstrual cycle. Blood glucose and serum insulin were determined in the fasting state. Independent of the diagnosis defined at the time of first evaluation, all the records of the patients were re-evaluated by the authors, and PCOS was diagnosed retrospectively based on the Rotterdam criteria.15 In accordance with the Rotterdam definition, the diagnosis of PCOS was established on the basis of at least two of the following three abnormalities: chronic anovulation, clinical or biochemical hyperandrogenism, and polycystic ovaries on ultrasonography.15–18
Two hundred thirty-three women fulfilled the requirements for the diagnosis of PCOS at their initial evaluation. Forty patients were lost during the 20-year follow-up period. The present study, therefore, reports on the follow-up of 193 women with PCOS.
The patients were included in a project designed to evaluate the long-term consequences of PCOS. It was anticipated that this project would continue for up to 30 years to observe age-dependent endocrine and metabolic changes of the disorder. The patients were re-evaluated every 5 years, and at each re-evaluation, the same clinical, hormonal, and ultrasonographic data were reassessed.
During this long period of time, the patients had various treatments but were off treatment for at least 3 months at the time of their re-evaluation. Most patients (n=148) were treated with one of several oral contraceptives. The duration of the treatment varied and ranged between 6 months and 10 years. In long-term users of oral contraceptives, treatment was intermittent depending on clinical circumstances. Metformin and antiandrogens were also used more sporadically; in most cases, these other treatments were prescribed in patients who had already used oral contraceptives. In a minority of women (n=11), no pharmacological treatment was used. Most obese women underwent dietary intervention for variable times during the study, but no specific lifestyle program was adopted.
The procedures carried out were in agreement with the Helsinki Declaration of 1975 and the study was approved by the University of Palermo Ethics Council. All participants gave their informed consent to participate in the study.
Hormone levels were quantified by well-established methods, which had been validated previously in our laboratory.19–22 All steroids were measured by specific radioimmunoassays after extraction using previously described methods. In all assays, intra-assay and interassay coefficients of variation did not exceed 6% and 15%, respectively.
Anovulation was defined as serum progesterone less than 3 ng/mL (less than 9.54 nmol/L). In patients with normal menses, at least two consecutive menstrual cycles were evaluated, and the finding of low levels of serum progesterone (less than 3 ng/mL) in both cycles confirmed the presence of chronic anovulation.21,22
Biochemical hyperandrogenism was defined as serum testosterone greater than 60 ng/dL (greater than 2.08 nmol/L), serum dehydroepiandrosterone sulfate 3 mg/L or greater (7.8 mmol/L or greater), or both. These values for the diagnosis of hyperandrogenism have been previously established in our population with the same assays.19
Increased serum 17-hydroxprogesterone was defined as serum values greater than 3 mg/L (greater than 9.1 nmol/L). In patients with mildly increased serum 17-hydroxprogesterone (less than 10 mg/L and greater than 3 mg/L), increased 17-hydroxprogesterone responses to adrenocorticotropic hormone administration (1 mg intravenously with blood samples at 0 minutes, 30 minutes, and 60 minutes) was required to diagnose or rule out nonclassical 21- or 11-hydroxylase deficiency.21 The quantitative insulin-sensitivity check index method was used to assess insulin resistance.23
Ovarian ultrasonography was performed by an experienced ultrasonographer on day 5 of the menstrual cycle. Both data obtained by abdominal and transvaginal ultrasound examinations were considered useful for the diagnosis. Ovarian volume was calculated by the formula π/6 (D1×D2×D3) in which the dimensions (D) of length, width, and thickness were used. The volume of both ovaries was assessed and the mean ovarian volume was calculated. The diagnosis of polycystic ovaries by ultrasonography was based on established criteria.16,17
In some women, because of clinical suspicion, urinary-free cortisol, serum prolactin, and thyroid-secreting hormone were measured by commercial radioimmunoassay methods to rule out confounding disorders. No such patients were included in this analysis.
Statistical analyses were performed using Statview 5.0. Univariate analyses were performed using the unpaired t test for the numeric variables, whereas the differences in the prevalence for the nominal variables were analyzed by the χ2 test.
Healthy control participants and women with PCOS were of a similar age (21.8±2 and 21.8±2 years) but women with PCOS had a higher BMI (26.6±6.7 compared with 21.5±5), waist circumference (89±14 compared with 74±6 cm), serum luteinizing hormone (LH) (8±4 compared with 4.5±1 milli-international units/mL), LH:follicle-stimulating hormone (FSH) ratio (1.5±0.6 compared with 1±0.4), serum total testosterone (74±26 compared with 31±11 ng/dL), serum dehydroepiandrosterone sulfate (2.7±1.2 compared with 1.8±0.5 micrograms/mL), and serum insulin (14.9±6 compared with 9.8±2 microunits/mL; P<.01) and significantly (P<.01) lower quantitative insulin-sensitivity check index values (0.327±0.02 compared with 0.358±0.01). Ovarian volume was significantly (P<.01) greater in women with PCOS (10.9±3.9 compared with 4.9±1.2 mL; P<.01).
The most common PCOS phenotype was the most severe phenotype—phenotype A (chronic anovulation, hyperandrogenism, and polycystic ovaries), which was found in 110 women (57% of the women with PCOS), followed by the ovulatory phenotype (hyperandrogenism, polycystic ovaries, and normal ovulatory cycles [phenotype C]), which was present in 51 women (26% of PCOS). Eighteen women (9%) had chronic anovulation and hyperandrogenism but normal ovaries (phenotype B), whereas the remaining 13 women (7%) had no hyperandrogenism but chronic anovulation and polycystic ovaries (phenotype D). In Table 1, the main clinical and hormonal data of the different PCOS phenotypes are depicted. Mean age was similar in all phenotypes of PCOS, whereas women with hyperandrogenism and anovulation, (phenotypes A and B) had significantly greater BMI, waist circumference, total testosterone, insulin, and lower quantitative insulin-sensitivity check index compared with the other PCOS phenotypes and control participants. The LH:FSH ratio was increased in the hyperandrogenic and anovulatory phenotypes (A and B) and in normoandrogenic PCOS (phenotype D) compared with women with ovulatory PCOS (phenotype C) and control participants. Women with ovulatory PCOS (phenotype C) had significantly higher values of testosterone and insulin and lower quantitative insulin-sensitivity check index when compared with control participants and normoandrogenic PCOS (phenotype D).
Ovarian volume was similar in women with phenotype A (mean±standard deviation 12.5±4.1 mL) and phenotype D (11.6±4 mL). In both groups, ovarian size was greater (P<.01) when compared with phenotype B (6.0±1.7 mL, P<.01). Ovarian volume in phenotype A was also larger when compared with ovulatory PCOS phenotype C (9.1±2.4 mL, P<.01), whereas there were no significant differences between normoandrogenic and ovulatory PCOS (phenotypes C and D).
In Table 2, the main clinical and endocrine data of the women with PCOS, observed during the different evaluations over the 20 years of follow-up, are presented. Body mass index, insulin, and quantitative insulin-sensitivity check index did not change during the 20 years of follow-up. However, a progressive rise of waist circumference (becoming significant after 15 years, P<.05) and a more rapid decrease of total testosterone and dehydroepiandrosterone sulfate (both becoming significant after 10 years, P<.05) were observed. The increase of waist circumference and the decrease of circulating androgens continued through the 20-year follow-up visit, when the greatest differences from baseline were found (Fig. 1). Serum LH and LH:FSH remained stable during the initial 15 years, whereas at the 20-year visit, a small but nonsignificant decrease of LH and the LH:FSH ratio was observed. Ovarian volume remained unchanged during the first 10 years, whereas after 15 years, at a mean age of 37.5 years, there was a trend to decreasing ovarian size, which became significant (P<.01) at the 20-year follow-up visit (Table 2).
After 20 years of observation, the number of patients with a previous diagnosis of PCOS who had ovulatory cycles increased from 52 to 85 women. In 18 of these patients, because of normalization of biochemical hyperandrogenism and no clinical signs of hyperandrogenism, the diagnosis of PCOS could no longer be made. The other patients had a phenotype consistent with ovulatory PCOS (phenotype C). Because of the changes with time, at the 20-year visit, the prevalence of the “classic” phenotypes of PCOS, A and B, was reduced (phenotype A: n=72; phenotype B: n=16); whereas the milder forms became as common as the classic forms (ovulatory PCOS, phenotype C: n=67; normoandrogenic PCOS [phenotype D]: n=20).
There were no significant changes at the 20-year visit in BMI, LH, LH:FSH, insulin, and quantitative insulin-sensitivity check index observed when the patients were divided up according to their phenotype. Similarly, waist circumference increased and androgens decreased significantly in all PCOS phenotype groups (Fig. 1), whereas significant changes in ovarian volume could only be found in phenotypes A, C, and D, but not in phenotype B.
Of the original 110 women diagnosed with phenotype A, 72 retained the same phenotype after 20 years, whereas two were diagnosed with phenotype B, 21 with phenotype C, seven with phenotype D, and in eight women, PCOS could no longer be diagnosed. Eighteen women were originally diagnosed with phenotype B. After 20 years of follow-up, four women could no longer be diagnosed with PCOS, and none of these women had another phenotype. Of the 52 women originally diagnosed with phenotype C, after 20 years, six women no longer could be diagnosed with PCOS. Thirteen women had been diagnosed with phenotype D initially. All these women retained this phenotype after 20 years.
All groups showed a decrease of androgens and ovarian size and an increase in waist circumference. However, the individual changes were quite variable. Within each group, no correlations were found between baseline levels and the absolute or percentage decrease of testosterone or ovarian volume. Although most patients had some treatment during the 20 years of follow-up, the variable durations of therapy, the differences in the various products, and the use of different products at different times over the 20 years prevented a comprehensive evaluation of the effects of the various treatments on the evolution of the syndrome with age.
However, we evaluated the differences observed between patients who were treated for at least 6 months with any oral contraceptive therapy (n=148) and those patients who did not use any therapy (n=11). Although the number of women not treated was small, no differences were found in the endocrine, ovarian, or clinical changes observed between the two groups, suggesting a lack of influence of oral contraceptives on the effects of aging in PCOS. Similarly, we did not find any difference in the evolution of changes with time between patients who were treated with metformin for at least 6 months (n=54) and those patients who did not use any therapy (n=11). Because the reporting of pregnancies during the 20 years of follow-up was sporadic, no data could be generated on whether pregnancy affected the natural evolution of the syndrome over time.
We have carried out a longitudinal study evaluating changes of clinical, hormonal, and metabolic patterns during a follow-up of 20 years in a large group of women with PCOS presenting with different phenotypes, Whereas at initial evaluation, the more severe phenotypes of anovulatory and hyperandrogenic women (phenotypes A and B) were prevalent, by age 40 to 45 years, the number of ovulatory patients increased and the mean values of serum androgens were significantly reduced. As a consequence, the milder phenotypes became as common as the severe phenotypes, and in a minority of patients, a clinical diagnosis of PCOS could no longer be made. The degree to which androgen levels decreased was similar in the various phenotypes and, therefore, although most women with mild hyperandrogenism became normal, many women with the more severe phenotypes (A and B) remained hyperandrogenic.
Although some cross-sectional studies have suggested similar results,3–8 the available data from these studies are limited. A potential concern with cross-sectional studies is that patients presenting at a younger age may have had more severe abnormalities such as higher levels of testosterone, thus artificially exaggerating the decline observed in women presenting with less severe abnormalities at an older age.
Our data confirm that in the fourth decade, ovulation becomes more common in women with PCOS, whereas serum androgens and ovarian size decrease. Previous studies have suggested that in addition to androgen, reductions in the overall follicular pool of the ovary helps to explain the more regular cycles in women with PCOS.24,25 Because of these changes, in 18 of the 193 women in the study, the diagnosis of PCOS could no longer be made and the milder phenotypes (ovulatory and normoandrogenic—C and D) became as common as the more severe phenotypes (anovulation and hyperandrogenism—A and B). Interestingly, the hormonal changes that determined this change in presentation began relatively early with a decrease of testosterone and dehydroepiandrosterone sulfate observed to occur after the third decade and then became more progressively pronounced. However, the mean level of total testosterone in the fourth decade, while followed, was still higher compared with healthy young control participants.
At the last visit for the purposes of this study, after twenty years of follow-up, we also observed a decrease in mean LH and LH:FSH ratio that, however, did not reach statistical significance. This was suggested to occur in a Dutch cohort of women with World Health Organization 2 anovulation presumed to predominantly have a diagnosis of PCOS.25 It is possible that prolonging the observation may lead to significant changes also in LH and the LH:FSH ratio. Similarly, ovarian size was significantly reduced at the 20-year visit.
On the contrary, we did not observe significant changes in the metabolic pattern, although waist circumference progressively increased. Changes in waist circumference may depend on age-related changes in body composition.26 There were no changes in body weight (BMI), insulin, or insulin resistance parameters observed. This does not preclude the possibility that increased metabolic derangements may occur with aging. After the 20 years of follow-up, the patients were still relatively young (mean age, 42 years) and the project is still ongoing to evaluate changes that may become evident later as the women reach menopause. A recent study has documented that certain metabolic changes do persist into menopause in women with PCOS.27
The reduction in androgens with aging in PCOS is most likely responsible for the changes in the phenotype over time. Most changes occurred in the largest group (phenotype A). In the other phenotypes, no conversions to other phenotypes occurred, but there was the inability to make the diagnosis in phenotypes B and C in four and six women, respectively. We would not expect women with phenotype C to convert to another phenotype over time, because even as androgens decrease, the women already have normal menstrual cycles by definition.
As more time passes, it will be of interest to determine how these women progress into menopause. More information on the influence of pregnancy on the phenotypes will also be the focus of future studies.
We have shown that in women with PCOS, circulating androgens begin to decrease steadily after the third decade and that this decrease continues progressively. This change is linked to a progressive reduction in the classic presentation of the syndrome with an increase of ovulatory cycles and the inability to diagnose the disorder in approximately 10% of women so diagnosed 20 years earlier. Ovarian volume was shown to be reduced by the fourth decade. On the contrary, the metabolic disorder may not improve, consistent with recent data,27 and the progressive increase of waist circumference may indeed signify the progressive nature of metabolic factors.
1. Carmina E, Longo RA, Rini GB, Lobo RA. Phenotypic variation in hyperandrogenic women influences the finding of abnormal metabolic and cardiovascular risk parameters. J Clin Endocrinol Metab 2005;90:2545–9.
2. Guastella E, Longo RA, Carmina E. Clinical and endocrine characteristics of the main polycystic ovary syndrome phenotypes. Fertil Steril 2010;94:2197–201.
3. Labrie F, Belanger A, Cusan L, Gomez J, Candas B. Marked decline in serum concentrations of adrenal C19 sex steroid precursors and conjugated androgen metabolites during aging. J Clin Endocrinol Metab 1997;82:2396–402.
4. Winters SJ, Talbott E, Guzick DS, Zborowski J, McHugh KP. Serum testosterone levels decrease in middle age in women with the polycystic ovary syndrome. Fertil Steril 2000;73:724–9.
5. Bili H, Laven J, Imani B, Eijkemans MJ, Fauser BC. Age-related differences in features associated with polycystic ovary syndrome in normogonadotrophic oligo-amenonorrheic infertile women of reproductive years. Eur J Endocrinol 2001;145:749–55.
6. Morán C, Knochenhauer E, Boots LR, Azziz R. Adrenal androgen excess in hyperandrogenism: relation to age and body mass. Fertil Steril 1999;71:671–4.
7. Birdsall MA, Farquhar CM. Polycystic ovaries in pre and post-menopausal women. Clin Endocrinol (Oxf) 1996;44:269–76.
8. Koivunen R, Laatikainen T, Tomas C, Huhtaniemi I, Tapanainen J, Martikainen H. The prevalence of polycystic ovaries in healthy women. Acta Obstet Gynecol Scand 1999;78:137–41.
9. Alsamarai S, Adams JM, Murphy MK, Post MD, Hayden DL, Hall JE, Welt CK. Criteria for polycystic ovarian morphology in polycystic ovary syndrome as a function of age. J Clin Endocrinol Metab 2009;94:4961–70.
10. Elting MW, Korsen TJ, Rekers-Mombarg LT, Schoemaker J. Women with polycystic ovary syndrome gain regular menstrual cycles when ageing. Hum Reprod 2000;15:24–8.
11. Fink RI, Kolterman OG, Griffin J, Olefsky JM. Mechanisms of insulin resistance in aging. J Clin Invest 1983;71:1523–35.
12. Stevens J, Katz EG, Huxley RR. Associations between gender, age and waist circumference. Eur J Clin Nutr 2010;64:6–15.
13. Taponen S, Martikainen H, Järvelin MR, Laiatinen J, Pouta A, et al.. Hormonal profile of women with self-reported symptoms of oligomenorrhea and/or hirsutism: Northern Finland birth cohort 1966 study. J Clin Endocrinol Metab 2003;88:141–7.
14. Hatch R, Rosenfield RL, Kim MH, Tredway D. Hirsutism: implications, etiology, and management. Am J Obstet Gynecol 1981;140:815–30.
15. Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod 2004;19:41–7.
16. Balen AH, Laven JS, Tan SL, Dewailly D. Ultrasound assessment of the polycystic ovary: international consensus definition. Hum Reprod Update 2003;9:505–14.
17. Carmina E, Orio F, Palomba S, Longo RA, Lombardi G, Lobo RA. Ovarian size and blood flow in women with polycystic ovary syndrome and their correlations with endocrine parameters. Fertil Steril 2005;84:413–9.
18. Carmina E. Mild androgen phenotypes. Best Pract Res Clin Endocrinol Metab 2006;20:207–20.
19. Carmina E, Stanczyk F, Chang L, Miles RA, Lobo RA. The ratio of androstenedione: 11 beta-hydroxyandrostenedione is an important marker of adrenal androgen excess in women. Fertil Steril 1992;58:148–52.
20. Carmina E. Prevalence of idiopathic hirsutism. Eur J Endocrinol 1998;139:421–3.
21. Carmina E, Lobo RA. Evaluation of hormonal status. In: Strauss JF III, Barbieri RL, editors. Yen and Jaffe's reproductive endocrinology: physiology, pathophysiology and clinical management. 6th ed. Philadelphia: Elsevier-Saunders; 2009. p. 801–23.
22. Carmina E, Rosato F, Jann ì A, Rizzo M, Longo RA. Extensive clinical experience: relative prevalence of different androgen excess disorders in 950 women referred because of clinical hyperandrogenism. J Clin Endocrinol Metab 2006;91:2–6.
23. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, et al.. Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 2000;85:2402–10.
24. Elting MW, Kwee J, Korsen TJ, Rekers-Mombarq LT, Schoemaker J. Aging women with polycystic ovary syndrome who achieve regular menstrual cycles have a smaller follicle cohort than those who continue to have irregular cycles. Fertil Steril 2003;79:1154–60.
25. Mulders AG, Laven JS, Eijkemans MJ, de Jong FH, Themmen AP, Fauser BC. Changes in anti-Müllerian hormone serum concentrations over time suggest delayed ovarian ageing in normogonadotrophic anovulatory infertility. Hum Reprod 2004;19:2036–42.
26. St-Onge MP, Gallagher D. Body composition changes with aging: the cause or the results of alterations in metabolic rate and macronutrient oxidation? Nutrition 2010;26:152–5.
27. Puurunen J, Piltonen T, Morin-Papunen L, Perheentupa A, Jarvela I, Ruokonen A, Tapanainen JS. Unfavorable hormonal, metabolic, and inflammatory alterations persist after menopause in women with PCOS. J Clin Endocrinol Metab 2011;96:1827–34.
© 2012 by The American College of Obstetricians and Gynecologists.