Fig. 11.1
Profile of daily urinary excretion of reproductive hormones for a representative eumenorrheic, ovulatory menstrual cycle. Classic characteristics include the E1G peak in the late follicular phase, the LH surge following the E1G peak, and rising PdG concentrations during the luteal phase. E1G estrone-1-glucuronide, PdG pregnanediol glucuronide, LH luteinizing hormone
The cascade of events surrounding the menstrual cycle commences with secretion of gonadotropin-releasing hormone (GnRH) from the arcuate nucleus and preoptic area of the hypothalamus which in turn stimulates the release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from gonadotroph cells of the anterior pituitary gland, the two gonadotropins that stimulate the production of estrogen and progesterone from the ovaries [9] (Fig. 11.2).
Fig. 11.2
HPO axis sequence of events related to the menstrual cycle. Neurons in the arcuate nucleus and preoptic area of the hypothalamus secrete GnRH which, in turn, stimulates the release of FSH and LH from the gonadotroph cells of the anterior pituitary gland. FSH and LH increase the production of estrogens progestins, and androgens by follicular granulosa and theca cells in the ovaries. During the luteal phase, the corpus luteum formed by the dominant follicle produces progesterone and estrogens. Typically, the ovarian hormones exert negative feedback on the anterior pituitary and hypothalamus, causing a decrease in the secretion of the gonadotropins. The negative feedback is depicted by the blue dashed lines. However, during the late follicular phase, rapidly rising estrogen concentrations exert positive feedback on the anterior pituitary and hypothalamus resulting in the LH surge. The positive feedback is depicted by the green solid lines. HPO hypothalamic–pituitary–ovarian, GnRH gonadotropin-releasing hormone, FSH follicle-stimulating hormone, LH luteinizing hormone
GnRH is known as the “master hormone” of reproduction due to its role as regulator of LH and FSH pulsatility [10]. Evidence from classic experiments conducted in rhesus monkeys [11, 12] demonstrated the rhythmic and acute secretory actions of GnRH. Typically, GnRH release occurs every 60–90 min, and, consequently, gonadotropin secretion occurs approximately once per hour from the anterior pituitary, paralleling the release of GnRH [8, 9, 13]. During the follicular phase, GnRH pulsatility and, therefore, LH and FSH pulsatility maintain a relatively high frequency [13]. Near the end of the follicular phase, the frequency and amplitude of GnRH pulses and, subsequently, LH and FSH pulses increase in response to the positive feedback of high estradiol concentrations [13]. However, at the end of the luteal phase, GnRH and LH pulsatility declines in response to negative feedback from progesterone [9, 13]. In turn, LH and FSH bind to receptors on the granulosa and theca cells of the developing ovarian follicle during the follicular phase and luteal cells during the luteal phase to produce estrogens, androgens, and progesterone [14].
During the late luteal and early follicular phase, FSH production increases, stimulating follicular growth and recruitment of the dominant follicle within the ovaries [13]. Production of the estrogen, estradiol, by the synergistic efforts of the theca and granulosa cells of the ovarian follicles also increases [13]; thus, during the follicular phase, estradiol concentrations gradually increase, upregulating the number of FSH receptors in the mature follicles and consequently increasing the action of FSH and the production of estradiol [13, 14]. During the mid-follicular phase, negative feedback by estradiol on the anterior pituitary prevents further increases in FSH and LH [9, 15]. Near the late mid-follicular phase to the end of the follicular phase, one follicle has achieved dominance and rapidly increases its production of estradiol while the other less-dominant follicles undergo atresia [13]. The rapidly rising concentrations of estradiol exert positive feedback in the preoptic area of the hypothalamus and on the gonadotroph cells of the anterior pituitary, sensitizing the cells to GnRH and stimulating the release of a bolus of LH after plasma estradiol concentrations exceed a threshold for at least 36 h [9, 11, 13, 15].
Therefore, the LH surge typically occurs 24–36 h after attainment of peak estradiol secretion and lasts for approximately 24–48 h [13]. In turn, the LH surge prompts proteolytic enzymes to digest the follicular wall, allowing the release of the oocyte from the dominant follicle and initiating ovulation, the event that separates the follicular and luteal phases [13]. Under the influence of LH, luteinization of the erupted follicle occurs, resulting in the formation of a corpus luteum, consisting of theca-lutein and granulosa-lutein cells [13]. These luteinized cells produce progesterone and, to a lesser extent, estradiol, which inhibit both the release of gonadotropins from the anterior pituitary and subsequent folliculogenesis [13]. In the absence of pregnancy-induced concentrations of human chorionic gonadotropin (hCG), the corpus luteum degenerates forming the corpus albicans and progesterone production declines at the end of the luteal phase, thereby removing the negative feedback on the anterior pituitary and hypothalamus [13]. FSH concentrations begin to increase again, recruiting another cohort of follicles for the subsequent cycle [13].
Therefore, in summary, a normal menstrual cycle demonstrates slowly increasing concentrations of FSH during the luteal-follicular transition and early follicular phase. Rising estradiol concentrations during the follicular phase exert negative feedback on the anterior pituitary and hypothalamus, resulting in no further increases of FSH and LH during the mid-follicular phase [9, 13, 15]. The peak in estradiol concentration mid-cycle triggers the LH surge, leading to ovulation and commencement of the luteal phase. The luteal phase is characterized by rising progesterone concentrations that decline near the end of the cycle as the corpus luteum degenerates (Fig. 11.1).
Within the uterus, the proliferative and secretory phases of the uterine cycle coincide with the follicular and luteal phases of the ovarian cycle. The proliferative phase involves a rebuilding of the functional layer of the endometrium after it has been shed during menses [16]. The cells of the zona basalis, that is, basal stromal cells, proliferate in response to rising concentrations of estradiol from the developing follicles [13]. During the late proliferative phase, hyperplasia of endometrial cells results in thickening of the endometrial wall such that the endometrium may increase in thickness from 0.5 to 5 mm [13]. Stimulated by progesterone from the corpus luteum, the secretory phase involves the glandular secretion of glycogen and increased vascularization to support the implantation of an embryo in the event that fertilization occurred [13, 16].
Decidual cells formed from stromal cells produce secretions in concert with the endometrial glands and create the zona compacta, the dense layer of upper endometrial cells [13]. The zona spongiosa, that is, the mid-layer of epithelial cells which consists of prominent endometrial glands, also becomes apparent during this phase [13]. In the absence of fertilization, progesterone and estrogen concentrations decline and the endometrium is deprived of hormonal support, causing the spiral arteries to constrict and destruction of the functional layer of the endometrium, i.e., the zona compacta and the zona spongiosa [13]. Eventually, as the upper two thirds of the endometrium degenerates, the arteries relax and menses begins [16]. As such, the menstrual phase of the uterine cycle is characterized by the loss of the functional layer of the endometrium as a result of ischemia and necrosis of endometrial tissues [13]. The innermost layer of the endometrium, the zona basalis, is all that remains at the end of the menstrual phase [13].
Thus, it is evident that both the ovarian and uterine cycles rely on proper functioning of the HPO axis and, subsequently, adequate hormonal concentrations, for normal menstrual function . Among exercising women with reproductive disturbances, the metabolic environment alters the HPO axis, leading to disruptions in the menstrual cycle that affect both the ovarian and uterine cycles and, in turn, influence reproductive potential.
Types of EAMD
EAMD occur along a spectrum ranging from mild to severe (Fig. 11.3). The least severe presentations of menstrual dysfunction include subtle menstrual disturbances, also known as subclinical menstrual disturbances that occur without a change in cycle length and are, therefore, frequently undetected; these subtle menstrual disturbances include LPD and anovulation . Severe menstrual disturbances, also known as clinical menstrual disturbances, exist at the pathological endpoint of the continuum and are characterized by long intermenstrual intervals (oligomenorrhea) or the absence of menstruation for more than 90 days which is referred to clinically as functional hypothalamic amenorrhea (FHA) .
Fig. 11.3
Spectrum of exercise-associated menstrual disturbances (EAMD). The subtle menstrual disturbance, luteal phase defects (LPD) , is the least severe EAMD, whereas functional hypothalamic amenorrhea (FHA), which represents a clinical menstrual disturbance, is the most severe EAMD
Subtle Menstrual Disturbances: LPD
LPD are characterized by adequate ovulatory function despite poor implantation and poor endometrial quality [1, 17, 18]. More specifically, LPD cycles are characterized by ovulatory cycles with normal and repeatable intermenstrual intervals but luteal phase dysfunction; they are defined by a short luteal phase length of < 10 days and/or inadequate progesterone production during the luteal phase [17, 19] (Fig. 11.4a). It has been suggested that a critical 3- or 5-day sum of mid-luteal progesterone concentrations can be used to identify inadequate progesterone exposure associated with LPD [19, 20].
Fig. 11.4
Profile of daily urinary excretion of reproductive hormones for subtle menstrual disturbances. a Representative menstrual cycle with a short and inadequate luteal phase defect. Classic characteristics include a luteal phase < 10 days in length and suppressed progesterone production during the luteal phase. b Representative anovulatory menstrual cycle. Classic characteristics include the lack of both a mid-cycle E1G peak and LH surge and the failure of PdG to rise during the latter part of the cycle, indicating the absence of ovulation. E1G estrone-1-glucuronide, PdG pregnanediol glucuronide, LH luteinizing hormone
As such, previous reports have used either a urinary pregnanediol glucuronide (PdG) peak of < 5 µg/ml or the sum of a 3-day mid-luteal PdG peak of < 10 µg/ml as indicators of an inadequate luteal progesterone production [5, 20]. Typically, women with LPD demonstrate a prolonged follicular phase in concert with the shortened luteal phase; thus, for example, an individual with a 28-day cycle and a 7-day luteal phase will have a 21-day follicular phase with an LH peak occurring on day 21 compared to women with normal ovulatory cycles in whom the LH peak and presumably ovulation occurs mid-cycle (days 12–14) for a 28-day cycle [1, 19].
The etiology of LPD has been proposed to be impaired folliculogenesis and oocyte maturation that results from disruptions of the reproductive axis [1, 17, 19]. Estrogen exposure during the follicular phase is suppressed among LPD cycles of exercising women compared to ovulatory cycles with normal luteal function [6]. Likewise, there is a delayed rise in FSH concentrations during the end of the preceding luteal phase, often referred to as the luteal-follicular transition, which is a critical time period for successful follicle recruitment [6]. A reduction in the concentration of the LH peak has also been reported in LPD cycles [5, 21]. Each of these hormonal alterations may contribute to abnormal function of the corpus luteum and, subsequently, suppressed progesterone concentrations [5, 6, 17, 21].
The determination of LPD in exercising women relies on the measurement of mid-cycle LH and daily progesterone concentrations in the luteal phase via daily urine or a timed serum sample during a single cycle; however, the monitoring of multiple consecutive cycles is advised for detection of LPD due to the inconsistency with which LPD cycles are observed in exercising women [5, 6]. For example, women may present with a normal, ovulatory cycle one month followed by an LPD or anovulatory cycle the next month. Inconsistent presentations of LPD and anovulation during consecutive cycles may also occur in the same individual. In fact, it has been reported that almost half (46 %) of exercising women present with inconsistent menstrual status; therefore, monitoring only one cycle may underestimate the incidence of menstrual disturbances among exercising women by 38 % [6]. Procedures for daily urine or serum sampling are costly and often not feasible; therefore, the detection of LPD in exercising women is difficult and the majority of women with LPD are often unaware of the presence of this subclinical menstrual perturbation. Notably, self-report and/or assessment of menstrual history alone will not detect LPD, thereby further contributing to the underestimation of the prevalence of menstrual disturbances among exercising women.
Subtle Menstrual Disturbances: Anovulation
Anovulation represents a subtle menstrual disturbance that is more severe than LPD. The hallmark characteristic of anovulation is the failure of follicular estrogen to rise concomitant with the lack of the mid-cycle LH surge and the subsequent failure to ovulate [5] (Fig. 11.4b). Similar to women with LPD, women with anovulatory cycles are, for the most part, experiencing regular intermenstrual intervals, making the identification of anovulation difficult. Due to the absence of ovulation and, consequently, the failure to produce a corpus luteum, progesterone concentrations do not increase during the latter part of the cycle. Therefore, anovulation has also been defined as the lack of an increase in urinary PdG from a 5-day follicular phase baseline or a peak PdG value < 2.49 µg/ml [5]. Both estrogen and progesterone concentrations have been reported to be lower in anovulatory cycles of exercising women compared to ovulatory cycles of exercising women, suggesting that disruptions in FSH and LH pulsatility contribute to anovulation [5, 6]. Adequate estrogen concentrations, however, allow for degeneration of the functional layer of the endometrium upon withdrawal of hormonal support at the end of the luteal phase, thereby resulting in normal menses [13].
Severe Menstrual Disturbances: Oligomenorrhea
Oligomenorrhea represents cycles with long and inconsistent intermenstrual intervals of 36–90 days that are often accompanied by 3–6 menses events per year [1, 22, 23] (Fig. 11.5a). This severe menstrual disturbance is perhaps the least understood and most difficult perturbation to interpret due to its inconsistent hormonal characteristics. An oligomenorrheic cycle may be ovulatory or anovulatory, and estrogen concentrations often produce erratic profiles during the extended cycle as follicles seek dominance [1].
Fig. 11.5
Profile of daily urinary excretion of reproductive hormones for severe menstrual disturbances. a Representative oligomenorrheic, anovulatory menstrual cycle. Classic characteristics include a cycle 36–90 days in length and an erratic hormonal profile. b Representative amenorrheic 28-day monitoring period. Classic characteristics include chronic suppression of E1G and PdG. E1G estrone-1-glucuronide, PdG pregnanediol glucuronide, LH luteinizing hormone
The etiology of oligomenorrhea in exercising women may or may not be hypothalamic in nature [22]. Oligomenorrhea can be associated with prolactin-secreting tumors, thyroidtoxicosis and other endocrinopathies, but most often, oligomenorrhea is associated with hyperandrogenism [22, 24–27]. Hyperandrogenism is often secondary to polycystic ovarian syndrome (PCOS) [28] , which is causally linked to infertility in women [29].
In exercising women, oligomenorrhea has been often associated with hyperandrogenism, but may also occur secondary to an energy deficit. Investigators have observed hyperandrogenism concomitant with elevated LH/FSH ratio and free androgen index, two additional markers of PCOS , among athletes with menstrual dysfunction [24–26, 30]. Rickenlund et al. [24] identified that a distinct group of athletes with menstrual dysfunction presented with hyperandrogenism, and upon comparison of the oligo-amenorrheic athletes with hyperandrogenemia (H-OAM) to oligo-amenorrheic athletes with normal androgen profiles (N-OAM), the H-OAM group demonstrated a higher LH/FSH ratio than the N-OAM group, indicating that the profile of reproductive hormones differed between the two groups.
Of interest, however, is that circulating concentrations of triiodothyronine (TT3), a marker of energy deficiency , were significantly lower in both the H-OAM and N-OAM groups compared to a control group of sedentary women, suggesting that both groups may have been in an energy-deficient state [24].
On the other hand, when assessing athletes based on type of menstrual disturbance, Rickenlund et al. [25] observed that 24-h diurnal secretion of testosterone was significantly elevated among oligomenorrheic athletes compared to amenorrheic and regularly menstruating athletes. In addition, amenorrheic athletes demonstrated reduced LH pulsatility, a surrogate marker of GnRH inhibition at the hypothalamus, compared to regularly-menstruating controls, whereas oligomenorrheic athletes demonstrated an LH pulse pattern similar to that observed in regularly-menstruating controls [25].
Therefore, oligomenorrheic athletes did not display the normal hormonal pattern typical of hypothalamic inhibition due to an energy deficiency as was observed in amenorrheic athletes, suggesting that other factors such as hyperandrogenism could be a mechanism underlying oligomenorrhea in athletes. As such, the etiology of oligomenorrhea among exercising women with hyperandrogenemia is ambiguous, thereby complicating the treatment of menstrual dysfunction among this subgroup of exercising women. Careful screening of oligomenorrheic exercising women is necessary to determine if the long, inconsistent cycles are due to an energy deficit or PCOS [22] .
Severe Menstrual Disturbances: FHA
At the extreme end of the menstrual disturbance continuum is FHA, the most severe menstrual disturbance that is associated with severe estrogen deficiency and typically defined as the absence of menses for at least 90 days [1, 23], although definitions have varied [23, 31]. FHA is typically classified as either primary or secondary in nature [27]. Primary amenorrhea is defined as the failure to menstruate by 15 years of age in girls with secondary sex characteristics [27]; whereas, secondary amenorrhea is the abnormal cessation of the menstrual cycle after menarche [27].
FHA among exercising women refers to menstrual dysfunction that is caused by disruptions in the hypothalamus due to energy conservation and is unrelated to other causes of FHA associated with the four-compartment model [27, 32]. Exercising women with FHA present with chronically suppressed estrogen and progesterone concentrations [5, 33, 34] (Fig. 11.5b). This suppression is most likely the result of impaired GnRH, LH, and FSH pulsatility that are, therefore, inadequate to stimulate ovulation from the ovary as well as appropriate proliferation and removal of the functional layer of the endometrium.
As such, the ovaries and uterus of amenorrheic women are largely quiescent with minimal production of reproductive hormones. FHA is associated with the most severe clinical sequelae such as low bone mineral density (BMD) [35, 36], poor bone quality [37], and cardiovascular consequences, including a poor lipid profile and endothelial dysfunction [38–40].
Prevalence of EAMD
The prevalence of menstrual disturbances among exercising women has been reported to range from 0 to 60 %, a large range that encompasses the prevalence of both subtle and severe menstrual disturbances [41]. The range in prevalence rates in exercising women is large because of the variations in definitions used and methods of assessment in exercising women [5, 6, 42–53]. The prevalence estimates, however, frequently exceed that observed in the general population of nonathletic women that is as low as 3–5 % [5, 54–56] .
Prevalence of Subtle Menstrual Disturbances
Due to the burdensome nature of investigating the presence of subtle menstrual disturbances, only a few investigators have reported their prevalence among exercising women [5, 6, 42–44] despite LPD and anovulation together representing the most common menstrual disturbances linked to exercise training [5, 6]. The prevalence of subtle menstrual disturbances is alarmingly high given that these disturbances are masked by regular intermenstrual intervals. Prevalence estimates range from 5.9 to 43.0 % [5, 6, 42, 44] and 12.0 to 30.0 % [5, 6, 44] for LPD and anovulation, respectively. Indeed, the ideal method of identifying subtle menstrual disturbances requires the measurement of daily urinary excretion of reproductive hormones over multiple consecutive cycles.
Based on reports from our lab which has undertaken the task of assessing multiple cycles among exercising women, we observed that 27 and 25 % of exercising women with self-reported eumenorrheic cycles (i.e., 26–35 days in length) presented with an LPD or anovulatory cycle, respectively [5]. Therefore, over half of exercising women presented with a subtle menstrual disturbance, compared to only 5 % of sedentary women (Fig. 11.6).
Fig. 11.6
Prevalence of subtle menstrual disturbances among sedentary and exercising women. a Proportion of sedentary women categorized as having ovulatory or abnormal (LPD or anovulatory) cycles. b Proportion of exercising women categorized as having ovulatory or abnormal (LPD or anovulatory) cycles. Exercising women compared with sedentary women: † indicates p = 0.050; § indicates p < 0.001. Reprinted with permission of Oxford University Press from De Souza et al. [5]
Similarly, upon evaluation of individual menstrual cycles among exercising women monitored for 1–3 menstrual cycles, 21 and 29 % of the cycles demonstrated evidence of an LPD and anovulation, respectively, representing 50 % of the 120 cycles assessed in exercising women [5]. Only 4 % of the cycles of sedentary women had a subtle menstrual disturbance, all of which were characterized by an LPD [5] (Fig. 11.7).
Fig. 11.7
Prevalence of subtle menstrual disturbances among individual cycles of sedentary and exercising women. a Proportion of cycles displaying subtle menstrual disturbances among sedentary women. b Proportion of cycles displaying subtle menstrual disturbances among exercising women. Cycles of exercising women compared with cycles of sedentary women: ‡ indicates p < 0.050; § indicates p < 0.001. Reprinted with permission of Oxford University Press from De Souza et al. [5]
Therefore, these results clearly demonstrate the high prevalence with which these largely underdiagnosed menstrual disturbances occur, most often indicative of an energy-deficient state and other underlying health concerns. The strength of our study lies in the daily urinary assessment of reproductive hormones, which provides a complete picture of the hormonal fluctuation throughout the cycle. Therefore, this methodology allows for a more accurate estimate of the prevalence of EAMD than can be obtained from relying solely on self-report measures that often underestimate EAMD prevalence. The frequency at which these “hidden” menstrual disturbances present in exercising women is cause for concern due to the negative impact of an energy deficit and menstrual disturbances on health outcomes and lack of symptomatic indicators that such disturbances are present.
Prevalence of Severe Menstrual Disturbances
Several investigators have evaluated the prevalence of the severe menstrual disturbances (FHA and oligomenorrhea) in female athletes, including both high school [48, 57–59] and adult women [5, 6, 45–47, 60–65]. The earliest prevalence estimates of clinical menstrual disturbances were evaluated in long-distance runners [49–53, 66], dancers [67, 68], and gymnasts [69], and in general, severe menstrual disturbances are documented at much higher rates in premenopausal exercising women than in sedentary women [54–56].
Based on these reports in female athletes and exercising women, the prevalence of primary and secondary amenorrhea ranged from 0 to 56.0 % (determined in 13 studies) [41] and 1 to 60.0 % (determined in 35 studies) [41], respectively; whereas, the range in prevalence of oligomenorrhea was 0.9–52.5 % (determined in 23 studies) [41]. In a recent report that assessed menstrual status in recreationally active women based on daily urinary steroid excretion, investigators observed that 7 % of exercising women presented with oligomenorrhea; whereas, 37 % were amenorrheic [5]. No sedentary women in the sample, however, presented with either oligomenorrhea or amenorrhea [5]. Therefore, menstrual disturbances among exercising women are relatively frequent, highlighting the need for awareness of the problem and its associated consequences in an effort to promote healthy exercise habits.
Changes in HPO Activity Associated with EAMD
Chronic energy deficiency targets the pulsatile secretion of GnRH from the arcuate nucleus of the hypothalamus . Disruptions in GnRH pulsatility often lead to changes in the frequency and amplitude of LH and FSH pulses, longer cycle length (particularly a longer follicular phase), reductions in average and peak luteal phase progesterone concentrations, and suppressed estradiol and progesterone [70]. It is believed that GnRH pulsatility, as governed by the pulse generator located in the hypothalamus [8], is sensitive to changes in the metabolic environment that are characteristic of an energy deficiency [7, 71]. (For a detailed description of metabolic adaptations that affect reproductive function , refer to Chap. 12). Thus, an energy deficit disrupts GnRH pulsatility, beginning the cascade of alterations in FSH and LH secretion, estrogen and progesterone production, and ultimately reproductive dysfunction.
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