© Springer Science+Business Media New York 2015
Emily S. Jungheim (ed.)Obesity and Fertility10.1007/978-1-4939-2611-4_22. Obesity and the HPO Axis
(1)
Department of Obstetrics and Gynecology, University of Colorado Denver, 12631 East 17th Avenue, Mail Stop B198-3, Academic Office Building 1, Room 4421, Aurora, CO 80045, USA
(2)
Department of Obstetrics and Gynecology, University of Colorado School of Medicine, Denver, CO, USA
Keywords
ObesityHPO axisInfertilityAndrogensEstradiolProgesteroneInhibinsGhrelinLeptinAdiponectinIntroduction
The obesity epidemic in the United States is accelerating. By 2015, approximately 41 % of US adults will have a body mass index (BMI) of greater than 30 kg/m2 [1]. Female adiposity is associated with irregular menses, ovulatory dysfunction, decreased fertility, and a high risk of obstetrical complications. While adiposity–subfertility association is well documented, the underlying pathophysiology remains poorly understood. Abnormalities of reproductive hormones have been studied as potential causes for the aforementioned disorders but a unified mechanism has not yet been determined. Studying the female reproductive axis is difficult because many hormones are secreted intermittently in pulses that cannot be directly observed. This review will examine the current literature concerning the impact of obesity on the hypothalamic–pituitary–ovarian (HPO) axis and female fertility.
Definitions
Obesity, defined by a BMI greater than 30 kg/m2, is becoming increasingly common with 35.7 % of all US adults being classified as obese based on the most recent National Health and Nutrition Examination Survey [2]. Traditionally, the reproductive effects of female obesity were attributed to anovulation and hyperandrogenism. These features, however, are characteristic of PCOS, which has an estimated prevalence of 2–8 % in reproductive age women [3]. Simple or nonsyndromic obesity is much more prevalent than PCOS and seems to have a different pathophysiology with respect to the obesity-related reproductive impairment. Most notably, PCOS is characterized by increased serum luteinizing hormone (LH) while obese women typically have overall lower serum LH. Obesity may modulate some aspects of pituitary physiology, such as the gonadotropin responsiveness to gonadotropin-releasing hormone (GnRH) [4]. While obesity can affect many aspects of PCOS, it is a cause of this syndrome and could certainly affect reproduction regardless of PCOS symptomatology [3]. In this review, we will focus on how obesity in the absence of PCOS affects the HPO axis.
Obesity and Fecundity
The relationship between female obesity and reproductive capacity of an individual, or fecundity, has been examined in several studies in a variety of populations in settings of assisted and unassisted conception. A prospective cohort study from the Netherlands studied the probability of conception among women presenting to a fertility clinic for artificial insemination. They found that women with higher waist–hip ratio as well as higher BMI were less likely to conceive than their counterparts with lower or normal metrics. There was no relationship between menstrual cycle length or regularity and obesity or body fat distribution, suggesting that a factor other than regular ovulation was responsible for this decreased probability of conception [5]. A retrospective cohort study from Norway also examined the effect of BMI on success of assisted reproductive technology (ART) treatment. Increased BMI was associated with a lower live birth rate, higher incidence of early pregnancy loss, increased FSH requirement, and fewer obtained oocytes [6]. Several other studies have examined fecundity in women not receiving any fertility treatment. A large, retrospective cohort study from the 7,327 US couples showed that women with higher BMI had a longer time to pregnancy than normal-weight subjects. This association remained when the analysis was restricted to women with regular menstrual cycles [7]. This implies that the lower fecundability seen in obese women is not simply related to increased probability of abnormal cycle length or anovulation. A Dutch study of ovulatory, subfertile women showed that obesity was associated with a lower probability of pregnancy compared to women with a BMI 20–29 kg/m2. For every BMI unit above 29 there was a 5 % decrease in probability of pregnancy over 1 year [8]. Recent findings from the Study of Women’s Health across the Nation indicate that obese adolescent girls are expected to have a threefold increased risk of lifetime nulliparity and a fourfold increased risk of lifetime nulligravidity [9].
Thus, most studies of obesity and fecundity suggest that obesity is associated with an increased time to pregnancy. The reasons behind this association are unclear. While obesity can be associated with an increased risk of abnormal menstrual cycle length [10], the reduced fecundity persists even when women with abnormal cycle length, and thus the vast majority of anovulatory subjects, are removed from the analysis. This suggests that obesity affects several different aspects of the HPO axis above and beyond a yes-or-no effect on ovulation.
Obesity and Central Reproductive Hormones
Luteinizing Hormone
Several studies have shown a relationship between luteinizing hormone (LH) and BMI. Women with higher BMI have decreased LH pulse amplitude and overall decreased serum LH compared to normal-weight controls [11]. A study by Bohlke and colleagues suggested an inverse relationship between BMI and LH levels in premenopausal women without polycystic ovarian syndrome (PCOS) [12]. Another study found lower LH levels in women with higher BMI (>23.4) during the follicular phase compared to their counterparts with women with the BMI below this somewhat artificial cutoff [13]. Similarly, other researchers found significantly lower follicular LH levels in overweight and obese women compared to normal-weight women during the early follicular phase [14]. Finally, a large study of perimenopausal women showed obese and overweight women had significantly decreased daily urinary LH throughout the menstrual cycle as compared to normal-weight women [15]. Notably, whole cycle and peak LH increase significantly in women who have undergone bariatric surgery compared to preoperative women [16]. As these women lost a significant amount of weigh postoperatively, these results suggest that obesity or an obesity-related condition is directly responsible for this suppressed LH. Overall, most studies suggest that obesity may lead to a decreased LH, particularly starting from early follicular phase of the menstrual cycle. One proposed mechanism to explain the decreased LH seen in obese women is that the decreased SHBG also seen in obese women [17] leads to increased free estradiol. Thus, it could be hypothesized that this increased level of free estradiol may exert exaggerated negative feedback on the pituitary, leading to diminished gonadotropin output.
Follicle-Stimulating Hormone
Similar to LH, several studies have also shown decreased levels of follicle-stimulating hormone (FSH) in obese women. Women with higher BMI had significantly lower FSH levels compared to normal-weight women throughout the menstrual cycle [13]. Total cycle FSH level was also found to be negatively correlated with BMI in perimenopausal women [15]. As with LH, a possible explanation is the increased free estradiol present in obese women due to suppressed SHBG production. Alternatively, reduced restraint from ovarian factors that normally exert negative feedback may also be at play as detailed below.
Obesity and Ovarian Hormones
Androgens
In perimenopausal women, BMI was positively correlated with total testosterone and free androgen index but negatively correlated with DHEAS and SHBG levels. Thus, obesity may be associated with an increase in ovarian androgen production but a decrease in adrenal androgen production as well as SHBG [17]. Another study found similar results among postmenopausal women with the metabolic syndrome [18]. Increased androgen effects in obese women could therefore be from two distinct but necessarily mutually exclusive mechanisms: increased ovarian production of androgens or increased free androgens present due to decreased SHBG. Both pathways remain plausible hypotheses and will need be carefully tested in light of recently developing data on the efficacy of androgen-increasing aromatase inhibition in treatment of female infertility.
Estradiol
Higher BMI may be associated with lower estradiol levels. Premenopausal obese women have lower serum estradiol than their normal-weight counterparts. However, postmenopausal obese women have significantly higher estradiol than normal-weight women [19]. This relationship in postmenopausal women was also noted in another study, which in addition found further increases in estradiol levels with the metabolic syndrome [18]. Not all studies have shown this trend towards lower estradiol levels in obese women. When estrone conjugates are measured in the urine throughout a menstrual cycle, there are no significant differences between different BMI categories [11, 15]. Notably, the latter two studies use urinary estradiol metabolites and the others used serum estradiol, which potentially may explain differences between the observed results.
Progesterone
Progesterone, similar to estradiol, seems to decrease with increasing BMI. Levels of pregnanediol glucuronide (Pdg), a metabolite of progesterone excreted in urine, are lower in obese perimenopausal women than in women with normal BMI [15]. A similar result was found in obese premenopausal women with normal cycles [11]. Postoperatively, women who underwent bariatric surgery and were ovulatory had significantly increased luteal Pdg secretion compared to preoperative women. Pdg levels in the postoperative group did not reach the level of normal controls, though it should be noted that the postoperative women still had significantly higher BMI than the normal-weight controls [16]. A larger recent study of 29 women has not demonstrated an improvement in luteal-phase quality after bariatric surgery [20]. However, the preponderance of evidence indicated that substantial weight loss after bariatric surgery is associated with improved ovulatory function, fertility, and pregnancy outcomes [19, 21].
Inhibins
Inhibins are a family of peptides produced by the ovary that are thought to regulate follicular development. Inhibin B, mainly produced by the granulosa cells of the preantral or small antral follicles, is decreased in overweight and obese women compared to normal-weight controls [14]. Similar results were found among perimenopausal women [19]. Notably, this relationship changes with the transition to menopause, with obese women having significantly higher inhibin B levels than normal-weight women [22]. The mechanism for decreased inhibin production in obesity is unclear, but implies that lower inhibin in obese women may reflect the harmful effect of obesity on folliculogenesis [23]. Further, obese women have a significant reduction in follicular inhibin B but NOT in the number of ovarian follicles. This suggests a functional rather than structural deficit [14]. This functional impairment suggests that the predominant impact of obesity is on granulosa cell function, rather than a large volume of distribution driving the reduced hormonal levels. Thus, obesity represents a paradox of reduced ovarian negative feedback restraint DESPITE decreased circulating FSH levels.
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