The female reproductive system is strongly influenced by nutrition and energy balance. It is well known that food restriction or energy depletion can induce suppression of reproductive processes, while overnutrition is associated with reproductive dysfunction. However, the intricate mechanisms through which nutritional inputs and metabolic health are integrated into the coordination of reproduction are still being defined. In this review, we describe evidence for essential contributions by hormones that are responsive to food intake or fuel stores. Key metabolic hormones—including insulin, the incretins (glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1), growth hormone, ghrelin, leptin, and adiponectin—signal throughout the hypothalamic–pituitary–gonadal axis to support or suppress reproduction. We synthesize current knowledge on how these multifaceted hormones interact with the brain, pituitary, and ovaries to regulate functioning of the female reproductive system, incorporating in vitro and in vivo data from animal models and humans. Metabolic hormones are involved in orchestrating reproductive processes in healthy states, but some also play a significant role in the pathophysiology or treatment strategies of female reproductive disorders. Further understanding of the complex interrelationships between metabolic health and female reproductive function has important implications for improving women’s health overall.
Reproduction is an energetically expensive process, and the energetic costs are largely borne by the females of many species. The mammalian female reproductive system is responsible for producing female gametes, facilitating their fertilization with sperm, supporting embryonic-fetal growth and development, and enabling the birth and nourishment of the offspring. These complex processes require a high level of communication between various organ systems, and so reproduction is under tight control of centrally produced hormones released by the hypothalamus and pituitary, as well as signaling factors produced by the placenta, developing embryo, and tissues of the reproductive system. Considering the high energetic requirements of gamete production, gestation, and lactation, it is clear that levels of food and energy stores are additional pieces of information that must be incorporated into the control of reproductive processes. Therefore, hormones that are classically defined by their metabolic roles are also critically important for regulating reproduction, including those which relay acute changes in ingestion and nutrient levels (e.g., insulin, the incretins, growth hormone, and ghrelin), as well as hormones that communicate stored metabolic fuel levels (e.g., leptin and adiponectin).
Vertebrate orexigenic and anorectic neuropeptides that are classified based on their effects on appetite also modify levels of gonadotropin hormones in the reproductive axis [1]. Many bird species breed seasonally, which restricts reproductive activity to periods when local food supply is optimal for supporting increased metabolic demands [2,3]. Food availability affects fecundity and the timing of sexual maturity in fishes, and female iteroparous fishes may skip a spawning season if nutrient levels are insufficient [4,5]. There are also insect and nematode species that can enter diapause states to reversibly suspend development and reproduction under unfavourable conditions. Entry into or recovery from diapause in these invertebrate organisms is orchestrated in part by evolutionarily conserved signaling systems that communicate nutritional status [6,7]. Mammals exhibit patterns of sexual dimorphism that are consistent with the concept that females are better suited for withstanding periods of food scarcity, which would increase chances of reproductive success in nutritionally-fluctuating environments [1]. For instance, in contrast with males, female mammals tend to favor energy storage over the capacity for rapid fuel mobilization, and are more prone to accumulate adipose mass in subcutaneous depots [8–10].
This is exemplified by physiological responses to food restriction and excessive energy expenditure, or conversely by the reproductive system disorders that are linked to overnutrition.
Energy deficiency caused by stress, low food intake, or strenuous exercise can result in a suppression of neuroendocrine signals that allow normal menstruation and ovulation. This deregulation is signified by a loss or alteration of gonadotropin hormone pulsatility, and leads to ovarian responses such as decreased estradiol production [11–13]. Low energy availability can thereby cause primary amenorrhea, a delay in menarche, or secondary amenorrhea, a temporary halt in natural menstrual cycling [14]. Studies in human populations exemplary of a negative energy balance have shed light on aberrant menstrual patterns. Ballet dancers [15,16] and athletes [17,18] engaged in high physical activity may have a delayed pubertal onset. Additionally, disordered eating, excessive exercise, or lifestyle stressors can cause menses loss in erstwhile normal-ovulatory women [19–22]. Temporary food deprivation or fasting can also induce a drop in gonadotropin levels and rise in cortisol [23–27]. Furthermore, women in poverty-stricken and/or strenuous labor-demanding societies experience increased risks of adult amenorrhea and lower birth rates [28–32].
Importantly, the ready availability of energy or metabolic fuels is more critical to reproductive fitness than adiposity per se. Food-deprived or over-exercised females can adjust food intake or activity to restore normal ovarian cyclicity and gonadotropin pulsatility before changes in adiposity or weight are evident [33–36]. Similarly, short fasting intervals halt ovarian cycles in Syrian hamsters without affecting adiposity, by reducing free fatty acid oxidation [37,38]. Maintaining glucose availability also preserves reproductive function in rodents and primates [39–43].
Amenorrhea and subfertility are not merely disorders of the reproductive system, but instead have broad physiological impacts. Just as a reduction in estrogen levels in postmenopausal women increases risks of cardiovascular disease [44], bone frailty [45], and neuropsychiatric disorders [46], a premenopausal estrogen deficiency caused by amenorrhea leads to compromised cardiovascular, skeletal, and mental health [47–51]. Thus, reproductive system responses to nutritional cues have far-reaching effects.
Undernutrition can suppress signals that allow reproduction, but chronic overnutrition is also associated with reproductive dysfunction. The recent prevalence of ultra-processed and low-satiating foods, combined with a more sedentary lifestyle, has led to a surplus of calories in everyday life [52–56]. Animal studies have shown that high-energy, high-fat diets interfere with reproductive function independent of obesity [57–60]. Additionally, obesity and a high body mass index are themselves associated with precocious menarche [61–65], menstrual cycle irregularities [66–69], infertility [70–73], miscarriage [74–76], and fetal abnormalities [77–82]. Diets that are high in refined carbohydrate also predict an earlier age of menopause [83,84].
Energy overload and reproductive dysfunction are also closely associated in the context of polycystic ovary syndrome (PCOS), the most prevalent female reproductive disorder [85,86]. The diagnostic features of PCOS include hyperandrogenism, menstrual cycle irregularities, and an accumulation of fluid-filled cysts in the ovaries [87,88]. However, PCOS has heterogeneous symptoms that often include obesity, elevated insulin, and/or a diminished capacity for glucose disposal [89,90]. These metabolic characteristics exacerbate the reproductive features of PCOS through such means as heightening testosterone levels [91–95]. Hypercaloric, high-fat diets also potentiate the traits of PCOS [96–98]. Women with PCOS tend to have difficulty conceiving, as well as a greater risk of pregnancy complications such as gestational diabetes, preeclampsia, or miscarriage [99–109]. PCOS is also associated with increased incidence of Type 2 diabetes [110–112], hypertension [110,113–117], high cholesterol [118–120], stroke [121,122], and cancer [123–126].
Weight loss [127–129], exercise [129–134], and bariatric surgery to limit food intake [135–140] are useful clinical tools for treating some aspects of the reproductive dysfunction associated with energy surplus. Lifestyle approaches such as balanced diet selections favoring whole grains, vegetables, fish, and unsaturated fats rather than saturated or trans fats are associated with increased fertility, improvements to PCOS symptoms, and beneficial impacts on other aspects of gynecologic health [141–144]. However, there is a lack of widespread awareness that diet has important implications for reproductive health (beyond effects on weight loss or perinatal health), and this is compounded by barriers preventing equal access to healthy diet options [143].
Effective management of nutritional and energy inputs is imperative for maintaining reproductive health. Nutrition and energy balance affect many aspects of reproductive health, including the menstrual cycle, fertility, pregnancy, fetal health, and age-related reproductive decline. This is due in part to the hormones that interpret food intake and fuel stores, which cooperate with cellular nutrient sensors to trigger the appropriate physiological responses for systemic energy homeostasis. These metabolic hormones engender changes across the reproductive axis, from the hypothalamus and pituitary to peripheral tissues of the female reproductive system (Figure 1).
Energetic deficits generally decrease levels of insulin, the incretin hormones (GIP and GLP-1), and leptin while also raising growth hormone, ghrelin, and adiponectin. Conversely, food ingestion and/or a chronic energy surplus causes the opposite shift in circulating levels of these hormones. Metabolic hormones act directly within the hypothalamus, pituitary, and ovaries to modulate reproductive processes. Their effects are thereby integrated into the reproductive axis, in which the hypothalamus and anterior pituitary communicate with the female reproductive system through the gonadotropins follicle-stimulating hormone (FSH) and luteinizing hormone (LH), while the ovaries in turn provide feedback via steroid hormones and other signaling factors.
The hypothalamic–pituitary–gonadal (HPG) axis comprises a system wherein the hypothalamus and anterior pituitary cooperate to centrally control gonadal maturity and function. Gonadotropin-releasing hormone (GnRH) is a tropic hormone secreted by a small subset of hypothalamic neurons in response to a suite of peripheral signals and neuronal messengers, including inputs from kisspeptin (Kiss1) neurons, astrocytes, γ-aminobutyric acid (GABA) neurons and pro-opiomelanocortin (POMC) neurons [145,146]. Pulses of GnRH released into portal circulation range in frequency from pulsatile to surge mode, depending on sex, age, and menstrual cycle phase [147–150]. Although the HPG axis is first established in utero, it is largely silenced until the initiation of nocturnal GnRH pulses during the onset of puberty [151,152]. Kisspeptin signaling is a key player in reactivating the HPG axis and initiating the pulsatile hypothalamic GnRH secretion required for sexual maturity and reproductive function [153–157]. Thereafter, rhythmic changes in frequency and amplitude of GnRH pulses are integral for controlling the differential secretion pattern of the two gonadotropin hormones, together with regulatory input by other systemic and paracrine factors.
Gonadotroph cells of the anterior pituitary produce the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) [158,159]. GnRH signaling induces differential expression of genes encoding LHβ and FSHβ subunits, in addition to regulating LH and FSH exocytosis [160]. In turn, FSH and LH exert controls over ovarian function, including steroidogenesis, follicular development, and ovulation. Together, forward-acting and feed-back regulatory loops facilitate a dynamic, nuanced reproductive axis that can be adjusted at multiple levels in response to internal and external conditions [161]. For instance, crucial information related to nutritional status and energy balance is incorporated into the reproductive axis via metabolic hormones exerting effects on GnRH production and release, gonadotropin secretion, and ovarian functions.
Oogenesis, folliculogenesis, and the production of steroid hormones and other signaling factors are tightly regulated ovarian processes that are responsive to inputs such as metabolic hormone si
