Elsevier

Steroids

Volume 64, Issue 6, June 1999, Pages 430-435
Steroids

Papers
Vitamin D and calcium dysregulation in the polycystic ovarian syndrome

https://doi.org/10.1016/S0039-128X(99)00012-4Get rights and content

Abstract

Over the past 30 years, numerous studies in invertebrates and vertebrates have established a role of calcium in oocyte maturation as well as in the resumption and progression of follicular development. Polycystic ovarian syndrome (PCO) is characterized by hyperandrogenic chronic anovulation, theca cell hyperplasia, and arrested follicular development. The aim of this observational study was to determine whether vitamin D and calcium dysregulation contribute to the development of follicular arrest in women with PCO, resulting in reproductive and menstrual dysfunction. Thirteen premenopausal women (mean age 31 ± 7.9 years) with documented chronic anovulation and hyperandrogenism were evaluated. Four women were amenorrheic and nine had a history oligomenorrhea, two of whom had dysfunctional bleeding. Nine had abnormal pelvic sonograms with multiple ovarian follicular cysts. All were hirsute, two had alopecia, and five had acanthosis nigricans. The mean 25 hydrovitamin D was 11.2 ± 6.9 ng/ml [normal (nl): 9–52], and the mean 1,25 dihydroxyvitamin D was 45.8 ± 18 pg/ml, with one woman with a 1,25 dihydroxyvitamin D <5 pg/ml (nl: 15–60). The mean intact parathyroid hormone level was 47 ± 19 pg/ml (nl: 10–65), with five women with abnormally elevated parathyroid hormone levels. All were normocalcemic (9.3 ± 0.4 mg/dl). Vitamin D repletion with calcium therapy resulted in normalized menstrual cycles within 2 months for seven women, with two experiencing resolution of their dysfunctional bleeding. Two became pregnant, and the other four patients maintained normal menstrual cycles. These data suggest that abnormalities in calcium homeostasis may be responsible, in part, for the arrested follicular development in women with PCO and may contribute to the pathogenesis of PCO.

Introduction

In 1935, Stein and Leventhal reported the association of enlarged polycystic ovaries with amenorrhea, hirsutism, and obesity [1]. Polycystic ovarian syndrome (PCO) has since been recognized to be one of the most common female endocrine disorders, characterized by hyperandrogenic chronic anovulation with infertility, irregular menses, dysfunctional uterine bleeding, acanthosis nigricans, and hirsutism [2]. The precise pathophysiologic mechanisms resulting in these endocrinologic disturbances are not known. The most widely accepted theory proposes that PCO is a self-perpetuating cycle of hormonal events with increased intra-ovarian concentrations of androgens, resulting in polycystic ovaries, theca cell hyperplasia, and arrested follicular cell development [3], [4], [5].

Recent animal investigations have established a role of calcium in oocyte activation and maturation, resulting in the resumption and progression of follicular development [6]. Attention had originally centered on the significance of calcium during oocyte activation at fertilization by either sperm or the divalent ionophore A23187. Based on evidence that the calcium ionophore A23187 activated the eggs of vertebrates and marine invertebrates by mediating calcium fluxes, Steinhardt et al. [7] proposed, in 1974, that calcium may have a universal role in egg activation. Since then, the importance of calcium in the regulation of both meiotic and mitotic cell division cycles in mammalian and non-mammalian oocytes has been of considerable interest [8]. The role of calcium oscillations during fertilization in the activation of both the non-mammalian and mammalian oocyte has been firmly established. Its role in triggering meiotic resumption and oocyte maturation in invertebrates is clear. In contrast, the precise role of calcium in oocyte differentiation and maturation in mammals is not as clearly defined, although it is strongly suggested by numerous animal investigations [9]. In mammals, maturation of the immature oocyte and the activation and fertilization of the mature egg are two separate events. Both may be regulated by changes in intracellular calcium.

Because of the importance of calcium in both oocyte activation and maturation, it was hypothesized that abnormalities in calcium homeostasis may, in part, underlie the pathogenesis of PCO. Disordered calcium regulation could be responsible for the follicular arrest manifesting as the reproductive and menstrual disturbances characterizing, in part, the PCO syndrome. The present investigation was conducted as an exploratory and observational trial, and provides evidence for this hypothesis.

Section snippets

Experimental

Premenopausal women between the ages of 18 and 50 years were enrolled in this study. Women were included if they met the 1990 National Institute of Health Consensus criteria [10] of polycystic ovarian syndrome with chronic oligomenorrhea/anovulation and signs of androgen excess (hirsutism, acne, alopecia). The following were exclusion criteria: ovarian androgen secreting tumors, adrenal androgen secreting tumors, Cushing’s syndrome, hyperprolactinemia, primary hyperparathyroidism, malignancy,

Results

Thirteen premenopausal women with documented chronic anovulation and hyperandrogenism were evaluated. Ages ranged from 21 to 41 years (31.1 ± 7.9). The weight of the women varied from 55 to 102 kg, with a mean body mass index of 30.6 kg/m2 (Table 1). Eleven women were Hispanic and two were Caucasian. None had a history of consuming dietary supplements or vitamins. All had evidence of hirsutism, three had acne, and two had alopecia. Five women had evidence of acanthosis nigricans. Nine had

Discussion

Polycystic ovarian syndrome appears to be confined exclusively to Homo sapiens. A similar paradigm in the rest of the animal kingdom is unknown. Infertility and arrested follicular development, however, are not exclusively human traits. They have been extensively studied in invertebrates and vertebrates. In this observational study, our results support the hypothesis that abnormalities in calcium homeostasis may be responsible for the arrested follicular development and the menstrual

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    Diagnostic criteria for polycystic ovary syndromeTowards a rational approach

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