Gonadotropins at menopause: the influence of obesity, insulin resistance, and estrogens Juan M. Malacara, Martha E. Fajardo, Laura E. Nava* Instituto de Investigaciones Me ´dicas, Universidad de Guanajuato, 20 de Enero 929, 37320 Leo ´n, Gto, Mexico Received 1 May 2000; received in revised form 1 September 2000; accepted 12 September 2000 Abstract Obese, postmenopausal women have lower FSH levels. To determine whether this is due to higher estrogen exposure, we compared feedback gonadotropin sensitivity and its relation to insulin resistance in four groups of obese and lean, postmenopausal women. Group one was treated with 400 mg troglitazone (TG) daily for two weeks; 150 clomiphene citrate (CC) was added daily for the second week. Group two received 150 mg CC daily for a week. Group three received 1000 mg metformin (MET) daily for two weeks, with 120 mg raloxifene (RAL) added during the second week. Group four received 120 mg RAL for a week. Before and after each period, a serum pool was obtained from samples taken every minute during a 10 ml interval. The women recruited for this study were categorized as obese or lean based on BMI  29 or BMI  29, respectively. Obese, menopausal women had lower FSH (45.5 IU/l) and LH (16.2 IU/l) values than those of lean (64.1 IU/l and 23.0 IU/l), but the obese menopausal women had higher leptin, DHEAS, glucose, insulin, and HOMA-IR levels. Log [FSH] was associated with BMI (r =-0.53, P  0.000001) and number of pregnancies (r =-0.37, P = 0.0009). TG treatment did not change HOMA-IR or gonadotropin levels, but DHEAS and androstenedione levels decreased significantly. CC alone or together with TG, diminished FSH (-7.9 and -9.2) and LH (-2.5 and -3.6) concentrations, with a greater reduction in lean women. MET reduced glucose and the HOMA-IR index without affecting gonadotropin or steroid levels. Conclusions: obese, menopausal women have lower FSH levels due to greater estrogen exposure, by mechanisms unrelated to insulin resistance. © 2001 Elsevier Science Inc. All rights reserved. Keywords: Menopause; Gonadotropins; Insulin resistance; Obesity; Steroids 1. Introduction Estrogen exposure during the menopause is a controver- sial issue related to diverse important health problems. Re- cent findings suggest significant estrogen exposure from external sources, such as phytoestrogens [1] found in certain foods or in products derived from industrial contamination [2]. Endogenous sources of estrogens at menopause are also possible. Extraovarian estrogens may derive from adrenal precursors. Several years ago, Poliak et al. [3] showed increased estrogen production in ovariectomized women after ACTH stimulation. Inactive adrenal precursors may be converted to active compounds in adipose tissue [4,5]. The peripheral conversion of inactive adrenal steroids to bioac- tive compounds is not accurately assessed in blood because of their rapid conversion to conjugated metabolites [6]. We previously found that FSH levels in postmenopausal women decrease with body mass index. An important pro- portion of obese, menopausal women have serum FSH levels below 30 IU/l [7]. This may indicate that they have significant estrogen exposure. This fact has important con- sequences when evaluating the indications for hormone replacement therapy, and the risk factors associated with estrogen deprivation. Therefore, it is important to define the hormonal conditions in obese, menopausal women. Obesity frequently induces insulin resistance and hyper- insulinemia. In the polycystic ovary syndrome, hyperinsu- linemia appears to play a role in altered androgen produc- tion [8]. This action of insulin may be mediated through an action on enzymes of the steroid synthesis such as the P450c17 [9], and in gonadal steroid metabolism [10]. In this condition, androgen excess may be reversed by reduc- ing insulin resistance through weight loss [11] or metformin administration [12]. Other studies, however, did not show an improvement of the androgen excess with metformin treatment [13]. Nestler et al. [14] reported an increase in the frequency of spontaneous ovulation and ovulation induced by clomiphene in metformin treated women with polycystic ovary syndrome. Troglitazone is another insulin sensitizing * Corresponding author. Tel.: +52-4-716-8354; fax: +52-4-716-8354. Steroids 66 (2001) 559 –567 0039-128X/01/$ – see front matter © 2001 Elsevier Science Inc. All rights reserved. PII: S0039-128X(00)00223-3