Endocrinologic features of oligomenorrheic adolescent girls*

Transcription

1 FERTILITY AND STERILITY Copyright <> 1986 The American Fertility Society Printed in U.SA. Endocrinologic features of oligomenorrheic adolescent girls* Rita Siegberg, M.D. t Carl Gustaf Nilsson, M.D. Ulf-Hakan Stenman, M.D. Olof Widholm, M.D. Department of Obstetrics and Gynecology, University Central Hospital, Helsinki, Finland The plasma concentrations of sex hormones were measured in 45 oligomenorrheic and 28 regularly menstruating adolescent girls. Testosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, estradiol, progesterone, luteinizing hormone, follicle-stimulating hormone, prolactin, and sex hormonebinding globulin levels were determined in blood samples collected during one menstrual cycle. The oligomenorrheic girls had significantly higher concentrations of luteinizing hormone, androstenedione, dehydroepiandrosterone-sulfate, and free testosterone than regularly menstruating girls. Sex hormone-binding globulin concentrations were significantly lower in the oligomenorrheic group. The oligomenorrheic girls were not obese. Signs of acne or hirsutism were absent or mild. Sixty-six percent of the oligomenorrheic cycles were ovulatory. The significance of the hormonal findings is discussed. Fertil SteriI46:852, 1986 Reports on the endocrinologic features of oligomenorrheic adolescent girls are scarce. Menstrual irregularities are thought to represent a natural stage of early postmenarcheal development. The frequencies of irregular bleedings are reported to be 20% and 40% during the first and fifth gynecologic years, respectively,! and the first menstrual cycles are anovulatory.2 Establishment of a positive feedback of estrogens necessary for the ovulatory luteinizing hormone (LH) surge occurs several years after menarche. 3 The pro- Received April 1, 1986; revised and accepted July 18, *Supported by a grant from the Signe and Ane Gyllenberg Foundation. treprint requests: Rita Siegberg, M.D., Department of Obstetrics and Gynecology, University Central Hospital, SF Helsinki 29, Finland. 852 Siegberg et al. Adolescent oligomenorrhea portion of ovulatory cycles increases with gynecologic age; 5 years after menarche, regular menstruations normally are established.2 Hence menstrual irregularities generally are considered to be a normal physiologic phenomenon that spontaneously subsides during the first few postmenarcheal years. However, polycystic ovarian disease (peod) is thought to have its origin during adolescent years. 4 It is therefore worthwhile studying adolescent endocrinology to discover possible early signs of disease, to prevent possible progression and future complications, such as obesity, hirsutism, persistent anovulation, and infertility problems. In a pilot study5 on the endocrinologic features of adolescent girls, we found elevated LH, androstenedione (a 4 A), testosterone (T), and free T concentrations in oligomenorrheic girls. The aim of this study was to confirm these findings by studying a greater number of adolescent girls. Fertility and Sterility

2 SUBJECTS MATERIALS AND METHODS The study subjects were adolescent girls admitted to an outpatient clinic for adolescent girls. Oligomenorrhea was defined as more than two cycles of > 37 days' duration during the previous 6 to 12 months. Regular menstruation was defined as cycles of 26 to 32 days' duration during the previous 6 to 12 months. Forty-five oligomenorrheic girls and 28 regularly menstruating girls were included in the study. Criteria for enrollment to the study were as follows: age between 14 and 20 years, age since menarche (gynecologic age) between 2 and 6 years, an exact history of menstrual pattern, normal health, normal height/weight ratio, no voluntary weight loss, no steroid hormone treatment during the past 6 months, and normal thyroid function, as evidenced by thyroxine and triiodothyronine uptake determinations. Gynecologic abnormalities were excluded with pelvic examination and a Papanicolau smear and, in some cases, ultrasound examination. The pubertal development stage for breasts and pubic hair was recorded with the use of Tanner's classification. 6 Blood pressure, height, and weight were measured. Acne and hirsutism were classified as normal or increased. Blood samples were collected between 8:00 A.M. and 3:00 P.M. once per week during one menstrual cycle. Serum samples were stored at - 20 C until assayed. Mean hormone levels were calculated with samples obtained on days 1 to 12, representing the follicular phase, and samples obtained during the last 12 days of the cycle, representing the luteal phase. A cycle was regarded as being ovulatory ifthe progesterone (P) concentration was> 10 nmovl. METHODS Levels of steroid hormones T, tl 4 A, dehydroepiandrosterone (DHEA), dehydroepiandrosteronesulfate (DHEA-S), estradiol (E 2), and P were determined with radioimmunoassays with the use of tritiated labeled steroids (Amersham International, Amersham, UK) and standards from Steraloids, Croydon, UK. Dextran-coated charcoal was used for separation. The antisera and methods used have been described. 7 The intraassay and interassay coefficients of variation of the as- says were 6% to 12% in the clinically relevant assay ranges. The reference ranges for fertile women are as follows: T, 0.7 to 2.8 nniolll; tl 4 A, 4.9 to 9.0 nmolll; DHEA, 10 to 30 nmol/l; and DHEA-S, 2.1 to 9.1,...molll. Sex hormone-binding globulin (SHBG) concentrations were determined with the use of a charcoal adsorption method. 8 The reference range for this method is 17 to 91 nmolll. Free T was calculated from values of SHBG and total T.9 The reference range for free T in women is 21 to 79 pmoill. Follicle-stimulating hormone (FSH) and LH levels were determined with radioimmunoassay with reagents obtained from Amersham International (FSH) and Biodata, Coisins, Switzerland (LH). The standard used for the FSH assay was the 2nd IRP 78/549; for the LH assay, the 1st IRP 68/40 was used. Prolactin (PRL) was assayed with reagents obtained from Biodata. Our reference range for PRL in women is 2 to 25,...gll. STATISTICAL METHODS The data were analyzed with the use of Biomedical Data Processing programs (BMDP Statistical Software of 1981, University of California, Los Angeles, CA).10 Means were compared with Student's t-test for independent samples (program 3D) and one- or two-way analyses of variance (program 7D). Contingency tables were tested by computing chi-square statistics (program 4F). Unless otherwise indicated, the results are expressed as the mean ± standard deviation. RESULTS There were no differences between the oligomenorrheic and regularly menstruating girls in mean age, age at menarche, gynecologic age, height, weight, or height/weight ratio (Table 1). Most ofthe oligomenorrheic girls (28 of 45) had had long cycles since menarche and had never had regular menstruations. Twelve oligomenorrheic girls had had a variable pattern of cycles, with cycles of normal length between the long cycles. Five of the oligomenorrheic girls had had regular cycles 1 to 5 years earlier. The mean lengths of the cycles during the previous 6 to 12 months and of the studied cycles were, in the oligomenorrheic girls, 54.2 ± 17.7 and 56.8 ± 30.1 days, respectively, and, in the regularly menstruating girls, 29.1 ± 1.6 and 29.6 Siegberg et al. Adolescent oligomenorrhea 853

3 Table 1. Mean Age, Age at Menarche, Gynecologic Age, Height, Weight, and Height/Weight Ratio in Adolescent Oligomenorrheic and Regularly Menstruating Girls a Age (yrs) Age at menarche Gynecologic age (yrs) Height (em) Weight (kg) Height/weight Oligomenorrheic group (n = 45) 17.5 ± ± ± ± ± ± 0.3 Control group (n = 28) 16.9 ± ± ± ± ± ± 0.2 ano significance between groups. Mean ± standard deviation. ± 2.5 days, respectively. The differences between groups were significant (P < 0.001). Pubertal development in the two groups was similar. All girls had reached breast and pubic hair development stage 4 or 5. Eighteen of the oligomenorrheic girls (40%) and 11 of the control girls (39%) were at breast developmental stage 4. Nine of the oligomenorrheic (20%) and eight of the regularly menstruating girls (28%) were at pubic developmental stage 4. The differences were not significant. Clinical signs of androgenicity were observed more often in the oligomenorrheic girls than in the regularly menstruating girls. Acne was observed in 9 of the oligomenorrheic girls (20.5%) and in 1 of the regularly menstruating girls (3.7%). The difference was significant (P < 0.05). Mild hirsutism was evident in 14 of the oligomenorrheic girls (31.8%) and in 1 of the control girls (3.7%). The difference was significant (P < 0.01). Significant differences in hormone concentrations were observed between the two groups during the cycle (Table 2). In the oligomenorrheic group, the LH concentration was significantly higher than in the control group, during both the follicular (P < 0.01) and the luteal phase (P < 0.01) of the cycle. The LHiFSH ratio, calculated from the values during the follicular phase, was 2.3 in the oligomenorrheic group and 1.5 in the regularly menstruating group. The difference was significant (P < 0.05). The a 4 A concentration was significantly higher in the oligomenorrheic group than in the control group, during both the follicular (P < 0.001) and the luteal phase (P < 0.01) of the cycle. Total T levels were not different between groups, but free T concentrations were higher in the oligomenorrheic girls than in the regularly menstruating girls during both the follicular phase (P < 0.001) and the luteal (P < 0.05) phase of the cycle. The SHBG concentration was lower in the oligomenorrheic group than in the control group during both the follicular (P < 0.05) and the luteal (P < 0.01) phase of the cycle. The DHEA and DHEA-S levels were higher in the oligomenorrheic girls than in the control group. The differences in DHEA concentration Table 2. Mean Hormone Concentrations During the Follicular and Luteal Phase of the Cycle in Oligomenorrheic and Regularly Menstruating Adolescent Girls a Oligomenor- Control Hormone Cycle phase rheic group group LH (lull) Follicular 11.9 ± 6.2b 7.8 ± 3.4 Luteal 12.0 ± 7.3 c 7.1 ± 3.7 FSH (lull) Follicular 5.7 ± ± 1.6 (28) (23) Luteal 3.5 ± ± 1.3 (39) (27) PRL (ngll) Follicular 10.1 ± ± 3.7 Luteal 10.1 ± ± 6.5 E2 (nmoul) Follicular 0.28 ± 0.12d 0.42 ± 0.34 Luteal 0.62 ± 0.31d 0.80 ± 0.35 P(nmoUl) Follicular 2.0 ± ± 0.8 Luteal 17.9 ± 16.1b 29.2 ± 17.6!J.4A (nmoul) Follicular 9.6 ± 2.9 c 6.8 ± 2.4 Luteal 8.4 ± 2.3b 6.7 ± 2.9 DHEA Follicular 20.3 ± 12.8d 14.4 ± 6.2 (nmoul) (27) (24) Luteal 14.7 ± ± 9.1 (39) (28) DHEA-S Follicular 7.4 ± ± 2.6 (ILmoUl) (28) (20) Luteal 7.7 ± 3.9b 5.5 ± 2.4 (38) (25) T (nmoul) Follicular 2.1 ± ± 0.6 (28) (23) Luteal 2.1 ± ± 0.8 FreeT Follicular 49.2 ± 21.3 c 29.6 ± 12.2 (pmoul) (26) (22) Luteal 46.2 ± 23.2b 32.5 ± 15.7 (36) (27) SHBG Follicular 40.5 ± 21.8b 55.6 ± 17.0 (nmoul) (27) (24) Luteal 42.0 ± 19.6b 58.0 ± 18.2 (38) (28) anumber in parentheses is number of samples. bp < 0.01 between the oligomenorrheic and the control group. cp < between the oligomenorrheic and the control group. dp < 0.05 between the oligomenorrheic and the control group. 854 Siegberg et ai. Adolescent oligomenorrhea Fertility and Sterility

4 during the follicular phase (P < 0.05) and in DHEA-S concentration during the luteal phase (p < 0.05) of the cycle were significant, the oligomenorrheic girls having higher concentrations. When the androgen levels of the oligomenorrheic girls were compared with adult reference values, 50% of the oligomenorrheic girls showed high concentrations of A4A, 12% total T, 4% free T, and 24% DHEA-S. There were no significant differences in the concentrations of FSH and PRL between the two groups. The levels ofe2 and P were significantly higher in the control group than in the oligomenorrheic group during the luteal phase of the cycle (P < 0.05 and P < 0.01, respectively). There were no differences in the levels of E2 and P during the luteal phase between the groups when only ovulatory cycles were compared. The frequencies of ovulatory cycles were 65.9% in the oligomenorrheic adolescent girls and 88.9% in the regularly menstruating adolescents. The difference was significant (P < 0.05). Four oligomenorrheic girls did not give blood samples during the last 12 days of the studied cycle. These cycles were excluded for calculation of ovulatory frequency. Five of the oligomenorrheic and one ofthe regular cycles showed a slight increase in P concentration, of between 4 and 9 nmoill. These cycles were regarded as being anovulatory. Table 3 shows the differences in hormone concentrations between oligomenorrheic girls with and without hirsutism. Hirsute oligomenorrheic girls had significantly higher concentrations of DHEA-S, during both the follicular (P < 0.05) and the luteal phase (P < 0.001) of the cycle, and significantly higher concentrations of total T (P < 0.05), free T (P < 0.05), and A4A (P < 0.001), during the luteal phase of the cycle, than the nonhirsute oligomenorrheic girls. There were no differences in the mean age, age at menarche, and gynecologic age between the hirsute and nonhirsute oligomenorrheic girls. The hirsute oligomenorrheic girls were slightly heavier and taller and had longer cycles than the nonhirsute oligomenorrheic girls, but the differences were not significant. The frequency of ovulatory cycles in the hirsute oligomenorrheic girls was 58.8% and in the nonhirsute girls 67.9%. The difference was not significant. Androgen and LH levels did not discriminate oligomenorrheic girls with and without acne. Table 3. Mean Height, Weight, Length of Cycle, and Hormone Concentrations During the Cycle in Oligomenorrheic Girls With and Without Hirsutism Hormone Hirsute Nonhirsute Mean ± SD Mean ± SD Height (kg) ± ± 6.9 Weight (em) 58.6 ± ± 6.9 Length of cycle 65.5 ± ± 27.2 (days) FSH (lull) Follicular 6.1 ± 0.9 Luteal 3.9 ± 1.9 LH (lull) Follicular 12.0 ± 4.4 Luteal 12.3 ± 8.4!:J. 4 A (nmolll) Follicular 10.4 ± 2.2 Luteal 10.3 ± 2.4a DHEA (nmolll) Follicular 22.3 ± 13.3 Luteal 19.2 ± 14.7 DHEA-S Follicular 9.2 ± 3.7 b (/Lmolll) Luteal 11.1 ± 3.8a T (nmolll) Follicular 2.3 ± 0.4 Luteal 2.4 ± 0.8 b Free T (pmolll) Follicular 55.2 ± 15.3 Luteal 60.4 ±29.8 b SHBG (nmolll) Follicular 34.8 ± 17.0 Luteal 36.3 ± 19.6 LHIFSH ratio Follicular 2.0 ± 0.6 ap < between hirsute and nonhirsute. bp < 0.05 between hirsute and nonhirsute. DISCUSSION 5.5 ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± 1.9 Our results show that oligomenorrheic adolescent girls have significantly higher concentrations of LH, A 4 A, and free T and significantly lower SHBG concentrations than regularly menstruating girls. This is in agreement with results of earlier studies. 1l,12 In this study, approximately 50% of the oligomenorrheic girls at some stage had elevated concentrations of A 4 A, but 25% also had elevated concentrations ofdhea-s. Venturoli et al12 reported elevated levels of DHEA, but not of DHEA-S, in adolescent girls with irregular menstruation. To our knowledge, this is the first study to demonstrate elevated DHEA-S concentrations in adolescent girls with oligomenorrhea. The hormonal pattern of the oligomenorrheic girls in this study resembles that seen in adult PCOD, but the hormone levels were not as pathologic as those in adult PCOD. The LH/FSH ratio of the adolescent oligomenorrheic girls was 2.3, which is higher than the mean normal midfollicular (1.3) but lower than that reported for adult PCOD patients (3.7).13 The adolescent oligomenorrheic girls did not show classical clinical features of PCOD. Clinical signs of androgenicity were absent or very mild, and the oligomenorrhe- Siegberg et at. Adolescent oligomenorrhea 855

5 ic girls had a higher frequency of ovulatory cycles than that reported for adult PCOD.14 Within the group of oligomenorrheic girls, those with hirsutism showed significantly higher levels of T, free T, d4a, and DHEA-S than nonhirsute oligomenorrheic girls. Statistically the most significant difference between the hirsute and nonhirsute girls was seen in DHEA-S concentrations, but levels of LH were similar (Table 3). The mean concentrations of d 4 A and DHEA-S were pathologic, compared with adult reference values. These findings show that elevated adrenal androgen production is fairly common in adolescent oligomenorrheic girls with hirsutism. Anovulation is a characteristic feature of the cycles of the first gynecologic years,15, 16 and the anovulatory cycles of adolescent girls are associated with increased serum concentrations of LH, T, and d4a.2, 16 The androgens of adolescent cycles are thought to be mainly of ovarian origin.2, 16 It has been suggested that ovarian cyclic androgen production plays an important role in the maturation of ovulatory mechanisms.2, 16 It has also been suggested that adolescent menstrual irregularities are a result of an immaturity of the estrogen-induced positive feedback mechanism, which develops several years after menarche.a The frequency of ovulations in the oligomenorrheic girls was fairly high (65.9%). A similar frequency in adolescent oligomenorrhea (59.3%) has been reportedp Thus the cause of the oligomenorrhea in adolescents does not seem to be an inoperative LH response to estrogens, but rather elevated levels of androgens and LH, as in adult oligomenorrhea caused by PCOD. Yen4 suggested that PCOD arises at menarche before the final establishment of cyclicity of the hypothalamic-pituitary-ovarian system, perhaps due to exaggerated adrenal androgen production, which can result in increased extraglandular estrogen production, inducing an elevated LHIFSH ratio, and as a result of this increased androgen production in the ovaries. It has also been suggested, by Mechanick and Futterweit,17 that PCOD develops during puberty from abnormal neural development in the brain, which generates inappropriately elevated LH secretion, leading to ovarian hyperandrogenemia. Zumoff et al. 18 showed that in adolescent PCOD patients pulsatile LH secretion occurs during the day rather than at night. We observed elevated DHEA-S levels in some adolescent oligomenorrheic girls, which could support the theory ofyen.4 However, elevated LH and d 4A levels were still more common, supporting the latter hypothesis. Oligomenorrhea is fairly common during adolescence, and it is possible that the high LH and androgen levels observed in the adolescent oligomenorrheic girls reflect a maturational condition2, 16 that subsides spontaneously with time. It is also possible that some of the oligomenorrheic girls had an early form of PCOD without marked clinical signs. Later, they may develop classical PCOD, with persistent anovulation and more pronounced clinical signs of hyperandrogenism. In unpublished observations,19 we noted both spontaneous recovery of adolescent hyperandrogenism and development of PCOD in adolescent oligomenorrheic girls, as also reported by others.20 Our study subjects were normally developed, healthy girls, with no signs of clinical abnormalities, seeking advice because of irregular bleedings. Their mean gynecologic age was 4.4 years. Ovulatory cyclicity normally is achieved within 5 years after menarche.2 This period normally is associated with relatively high androgen levels.16 Our study shows a fairly high frequency of ovulatory cycles in the oligomenorrheic girls, despite higher androgen and LH levels than in regularly menstruating girls. On the basis of these results, we suggest that healthy adolescent girls with oligomenorrhea be managed mostly with expectance for regularity of the cycle to occur. If there are clinical signs of hyperandrogenism, even mild, further examinationsfor adrenal and ovarian hyperandrogenic states, such as PCOD or late onset adrenal enzyme defects, should be performed. In the frequent case of need for contraceptives by adolescent girls, treatment with low-dose oral contraceptives seems to be reasonable for lowering both adrenal and ovarian androgens. 5 REFERENCES 1. Widholm 0, Kantero R-L: Menstrual pattern of adolescent girls according to chronological and gynecological age. Acta Obstet Gynecol Scand (Suppl) 14:19, Apter D, Vihko R:" Hormonal patterns of the first menstrual cycles. In Adolescence in Females, Edited by S Venturoli, C Flamigni, JR Givens. Chicago, Year Book Medical Publishers, 1985, p Reiter EO, Kulin H, Hammond SM: The absence of positive feedback between estrogens and luteinizing hormone in sexually immature girls. Pediatr Res 8:740, Yen SSC: Polycystic ovary syndrome. Clin Endocrinol (OxO 12:177, Siegberg et at. Adolescent oligomenorrhea Fertility and Sterility

6 5. Siegberg R, Nilsson CG, Stenman U-H, Widholm 0: Sex hormone profiles in oligomenorrheic adolescent girls and the effect of oral contraceptives. Fertil Steril41:888, Tanner JM: The development of the reproductive system. In Growth at Adolescence, Second Edition, Oxford, Blackwell Scientific Publications, 1962, p Koskimies la, Andersson BM, Stenman U-H, Laatikainen TJ: Effect of clomiphene on serum androgens and follicle development in chronic hypothalamic anovulation and in polycystic ovaries. Infertility 5:51, Hammond GL, Liihteenmiiki PLA: A versatile method for/ the determination of serum cortisol binding globulin and sex hormone binding globulin binding capacities. Clin Chim Acta 132:101, Vermeulen A, Stoica T, Verdonck L: The apparent free testosterone: an index of androgenicity. J Clin Endocrinol Metab 33:759, Dixon WJ, Brown MB, Egelman L, Frane JW, Hill MA, J ennrich RJ, Toporek JD: BMDP Statistical Software. Berkeley, University of California Press, 1985, p Emans SJ, Grace E, Goldstein DP: Oligomenorrhea in adolescent girls. J Pediatr 97:815, Venturoli S, Porcu E, Fabrini R, Paradisi R, Magrini C, Orsini LF, Ruggeri S: Endocrine profiles and ovarian aspects in adolescent menstrual abnormalities. In Adolescence in Females, Edited by S Venturoli, C Flagmini, J Givens. Chicago, Year Book Medical Publishers, 1985, p Givens JR, Andersen RN, Wiser WL, Fish SA: Dynamics in suppression and recovery of plasma FSI:I~ UI, anrostenedione and testosterone in polycystic ovarian disease using an oral contraceptive. J Clin Endocrinol Metab 38:727, GoldzieherJW, Axelrod LR: Clinical and biochemical features of polycystic ovarian disease. Fertil Steril 14:631, Metcalf MG, Skidmore DS, Lowry GF, Mackenzie JA: Incidence of ovulation in the years after the menarche. J Endocrinol 97:213, Vihko R, Apter D: The role of androgens in adolescent cycles. J Steroid Biochem 12:369, Mechanick JI, Futterweit W: Hypothesis: Aberrant puberty and Stein-Leventhal syndrome. Int J Fertil 29:35, Zumoff B, Freeman R, Coupey S, Saenger P, Markowitz M, Kream J: A chronobiologic abnormality in luteinizing hormone secretion in teenage girls with the polycysticovary syndrome. N Engl J Med 309:1206, Siegberg R: Unpublished data 20. Moll GW, Rosenfield RL: Plasma free testosterone in the diagnosis of adolescent polycystic ovary syndrome. J Pediatr 102:461, 1983 Siegberg et ai. Adolescent oligomenorrhea 857