20 YEARS OF LEPTIN: Role of leptin in human reproductive disorders

in Journal of Endocrinology

Leptin, as a key hormone in energy homeostasis, regulates neuroendocrine function, including reproduction. It has a permissive role in the initiation of puberty and maintenance of the hypothalamic–pituitary–gonadal axis. This is notable in patients with either congenital or acquired leptin deficiency from a state of chronic energy insufficiency. Hypothalamic amenorrhea is the best-studied, with clinical trials confirming a causative role of leptin in hypogonadotropic hypogonadism. Implications of leptin deficiency have also emerged in the pathophysiology of hypogonadism in type 1 diabetes. At the other end of the spectrum, hyperleptinemia may play a role in hypogonadism associated with obesity, polycystic ovarian syndrome, and type 2 diabetes. In these conditions of energy excess, mechanisms of reproductive dysfunction include central leptin resistance as well as direct effects at the gonadal level. Thus, reproductive dysfunction due to energy imbalance at both ends can be linked to leptin.

Abstract

Leptin, as a key hormone in energy homeostasis, regulates neuroendocrine function, including reproduction. It has a permissive role in the initiation of puberty and maintenance of the hypothalamic–pituitary–gonadal axis. This is notable in patients with either congenital or acquired leptin deficiency from a state of chronic energy insufficiency. Hypothalamic amenorrhea is the best-studied, with clinical trials confirming a causative role of leptin in hypogonadotropic hypogonadism. Implications of leptin deficiency have also emerged in the pathophysiology of hypogonadism in type 1 diabetes. At the other end of the spectrum, hyperleptinemia may play a role in hypogonadism associated with obesity, polycystic ovarian syndrome, and type 2 diabetes. In these conditions of energy excess, mechanisms of reproductive dysfunction include central leptin resistance as well as direct effects at the gonadal level. Thus, reproductive dysfunction due to energy imbalance at both ends can be linked to leptin.

Introduction

In 1974, Frisch proposed that the ability to reproduce requires a certain threshold of body fat to serve as the minimal store of energy necessary for ovulation, menstruation, and intended pregnancy (Frisch & McArthur 1974). Leptin eventually emerged as the predominant candidate linking adipose tissue, energy availability, and reproductive function (Chan & Mantzoros 2005, Mantzoros et al. 2011). Leptin is a hormone produced primarily in adipose tissue, and concentrations of leptin are directly proportional to amount of body fat (Considine et al. 1996, Yannakoulia et al. 2003, Hamnvik et al. 2011). More importantly, leptin concentrations are very sensitive to energy deprivation – 3 days of fasting decreases the concentrations to 10% of baseline (Chan et al. 2003). Women with hypothalamic amenorrhea (HA), which is a state of chronic energy deprivation from excess energy expenditure, stress, and/or insufficient nutritional intake, also have hypoleptinemia (Miller et al. 1998, Andrico et al. 2002). HA is characterized by dysfunction of the hypothalamic–pituitary–gonadal (HPG) axis, leading to anovulation and cessation of menstrual cycles in the absence of organic disease. Treatment with leptin has been found to restore reproductive function in these women (Welt et al. 2004, Chou et al. 2011). On the opposite spectrum, hyperleptinemia seen in obesity may play a role in hypogonadism and subfertility due to the development of leptin resistance, akin to insulin resistance. Thus, the regulatory effect of leptin on reproductive function appears to be U-shaped, with a protective role at low concentrations and pathological at high concentrations (Fig. 1; Table 1).

Figure 1

Download Figure

Figure 1

Schematic illustration of the interactions of leptin with the hypothalamic–pituitary–gonadal axis. Leptin stimulates POMC/CART and Glut neurons and inhibits AgRP/NPY and GABA neurons to modulate reproduction centrally. At the ovaries, leptin can have different effects depending on the metabolic status. AgRP, agouti-related peptide; CART, cocaine and amphetamine-regulated transcript; FSH, follicle-stimulating hormone; GABA, gamma-aminobutyric acid; Glut, glutamate; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; NKB, neurokinin B; NPY, neuropeptide Y; PMV, ventral premammillary nucleus; POMC, proopiomelanocortin.

Citation: Journal of Endocrinology 223, 1; 10.1530/JOE-14-0245

Table 1

Effect of leptin treatment in disorders associated with leptin deficiency and excess

DisorderReproductive dysfunctionEffect of leptin treatment
Leptin deficiency
 Congenital leptin deficiencyDelayed/arrested pubertyPermits onset of puberty in appropriately aged children
Hypothalamic hypogonadismIncreases LH levels
Menstrual abnormalities from luteal phase defect to amenorrheaRestores menses
Dramatically decreases weight, food intake, and appetite
Improves insulin resistance
 Lipodystrophy (women)Enlarged, polycystic ovariesDecreases free testosterone levels
HyperandrogenismIncreases SHBG levels
InfertilityIncreases LH response to GnRH
Hyperinsulinemia, insulin resistanceNormalizes menses
Normal pubertal onsetImproves insulin resistance
 Hypothalamic amenorrheaLow amplitude/frequency of GnRH pulsesIncreases levels of LH, estradiol, progesterone
Low/normal LH, FSH levelsIncreases ovarian volume and endometrial thickness
Low estradiol levelsIncreases number of dominant follicles and maximal follicular diameter
AnovulationRestores ovulation in 40%
AmenorrheaRestores menses in 70%
Hyperactive HPA axisIncreases cortisol levels
Sick euthyroid syndrome-like pictureIncreases thyroid hormone levels
Growth hormone resistanceIncreases levels of free IGF1
Improves bone mineral density
 Type 1 diabetesHypogonadotropic hypogonadism, infertility with uncontrolled diseaseIn mice models
 Restores Kiss1 gene expression, normalizes LH and sex steroids
 Improves glucose control and variability
Leptin excess
 Common obesityHyperinsulinemia, insulin resistanceModest weight loss, if any
Increased levels of inflammatory markers, free fatty acids
Decreased SHBG levels
Hypogonadotropic hypogonadism
Subfertility
 Polycystic ovarian syndromeSame as common obesity plusUnknown
 Hyperandrogenism
 Increased LH levels
 Polycystic ovaries
 Type 2 diabetesSame as common obesityNo clinically significant change in weight, A1c, or inflammatory markers

FSH, follicle-stimulating hormone; GnRH, gonadotropin-releasing hormone; HPA, hypothalamic–pituitary–adrenal; IGF1, insulin-like growth factor 1; LH, luteinizing hormone; SHBG, sex hormone binding globulin.

Leptin in normal reproductive life

Puberty

Similar to reproductive function, puberty has also been described to be ‘metabolically gated’ as a means to prevent fertility in conditions of energy insufficiency (Sanchez-Garrido & Tena-Sempere 2013). By signaling adequate energy stores, leptin was initially thought to be the trigger for the pubertal maturation. In girls, age at menarche has been found to be inversely related to serum concentrations of leptin and body fat (Matkovic et al. 1997). In both girls and boys, leptin concentrations rise before pubertal transition, followed by an initial increase of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and then sex steroids (Garcia-Mayor et al. 1997, Mantzoros et al. 1997a). In girls, however, leptin concentrations continue to rise, likely due to stimulatory the effects of estrogen, while leptin concentrations decrease in boys, despite increasing BMI, due to the inhibitory effects of testosterone (Garcia-Mayor et al. 1997, Mantzoros et al. 1997a, Rosenbaum & Leibel 1999). Leptin, however, is currently thought to have a more permissive role in pubertal maturation, as the administration of exogenous leptin alone could not trigger early puberty in patients with congenital leptin deficiency (Farooqi et al. 2002). Thus, it is unlikely that the early onset of puberty observed in obese children can be attributed to hyperleptinemia alone, especially because hyperleptinemia is associated with its resistance or tolerance.

More recently, KISS1 neurons in the arcuate nucleus (ARC) have been attributed as the ultimate gatekeepers of puberty, through which multiple metabolic input converge in addition to leptin (Sanchez-Garrido & Tena-Sempere 2013). Leptin may directly and indirectly stimulate these neurons to secrete kisspeptins that then stimulate gonadotropin-releasing hormone (GnRH) neurons (Sanchez-Garrido & Tena-Sempere 2013); leptin itself cannot stimulate GnRH neurons as they do not express leptin receptors (Quennell et al. 2009). However, the direct effects of leptin on KISS1 neurons do not seem to be required for puberty, as the deletion of leptin receptors from KISS1 neurons does not seem to affect pubertal timing (Donato et al. 2011). Furthermore, the selective expression of leptin receptors on only KISS1 neurons did not result in pubertal development (Cravo et al. 2013). In addition to leptin, neurokinin B, which is co-expressed with kisspeptins, has also been found to convey metabolic information to KISS1 neurons in a stimulatory autocrine/paracrine manner, which is also important for the initiation of puberty (Navarro et al. 2012, Pinilla et al. 2012). Outside of KISS1 neurons in the arcuate nucleus, leptin may also act on glutamatergic neurons in the ventral premammillary nucleus, which has also been shown to stimulate GnRH neurons during the development of puberty (Elias 2012).

Reproductive function

As in puberty, the effect of leptin on reproductive function depends on the metabolic state and involves a large network of neurons, converging at the hypothalamus, which allows for redundancies (Elias & Purohit 2013). Intracerebroventricular administration of leptin stimulates LH secretion in feed-restricted, but not well-nourished, ovariectomized mammals (Henry et al. 1999, 2001, Morrison et al. 2001, Amstalden et al. 2002). Again, the complex metabolic regulation of reproduction likely centers around the KISS1 neurons, which receive input from multiple hormonal signals, including leptin, ghrelin, neuropeptide Y (NPY), melanocortins, insulin, and insulin-like growth factor (Pinilla et al. 2012). Although leptin inhibits neurons that produce agouti-related peptide (AgRP) and NPY and stimulates neurons to secrete melanocortins (processed from proopiomelanocortin (POMC)) to decrease satiety and food intake (Cowley et al. 2001), KISS1 neurons appear to have their own reciprocal innervations with AgRP/NPY and POMC neurons (Backholer et al. 2010). AgRP antagonizes melanocortin receptors, resulting in LH inhibition in female animal studies (Watanobe et al. 1999, Schioth et al. 2001, Vulliemoz et al. 2005), while the effects of NPY on gonadotropins have been contradictory and seem to depend on the sex steroid milieu (Kalra et al. 1987, McDonald et al. 1989, Sabatino et al. 1989, Reznikov & McCann 1993, Urban et al. 1996, Jain et al. 1999, Elias & Purohit 2013). Outside the arcuate nucleus, leptin also stimulate glutamatergic neurons in the ventral premammillary nucleus and steroidogenic factor 1 neurons in the ventromedial nucleus of the hypothalamus to modulate reproductive function (Elias & Purohit 2013).

Leptin also seems to have redundant signaling pathways to centrally modulate reproductive effects. Although phosphorylation of signal transducer and activator of transcription 3 (STAT3) by leptin is critical for body energy homeostasis, it is not critical for reproductive function. The selective deletion of leptin-induced STAT3 signaling in female mice results in obesity and hyperphagia, but they maintain fertility (Bates et al. 2003). Similarly, selective deletion of leptin-induced phosphoinositide 3-kinase (PI3K) activity also results in fertile mice, despite features of obesity, glucose intolerance, and insulin resistance (Sadagurski et al. 2012, Elias & Purohit 2013). Mammalian target of rapamycin (mTOR) has been proposed to be an intracellular energy sensor and seems to be an important mediator of leptin signaling for reproductive function (Roa et al. 2009, Codner et al. 2012). Chronic activation of mTOR has been shown to partially reverse hypogonadism in caloric-restricted prepubertal female mice, while the blockade of mTOR activity blunts the positive effects of leptin on puberty in these mice (Roa et al. 2009).

Finally, leptin has also been found to have both stimulatory and inhibitory effects at the levels of the pituitary and gonads (Yu et al. 1997a,b, Agarwal et al. 1999, Tena-Sempere et al. 1999, 2000, Karamouti et al. 2009), and the effect of leptin may depend on metabolic status and sensitivity to leptin (Tena-Sempere 2007, Bluher & Mantzoros 2007). This is further discussed below in the clinical context of hyperleptinemia associated with type 2 diabetes mellitus and polycystic ovarian syndrome (PCOS).

Pregnancy

Concentrations of leptin rise continuously throughout pregnancy, fall considerably after birth, and then return to normal 6 weeks postpartum (Schubring et al. 1998). Although leptin concentrations correlate significantly with BMI during early pregnancy, the correlation coefficients drop with increasing gestational age until after delivery (Schubring et al. 1998). The additional source of leptin may be from the placenta and is regulated by human chorionic gonadotropin (hCG) and estradiol (Chardonnens et al. 1999, Maymo et al. 2009, Tessier et al. 2013). In pregnant rodents, central administration of leptin results in reduced food intake until mid-pregnancy when central resistance to leptin develops (Johnstone & Higuchi 2001, Mistry & Romsos 2002). In addition to an increase in plasma leptin-binding activity seen in pregnant rats (Seeber et al. 2002), progesterone, prolactin, and placental lactogen may also contribute to leptin resistance (Grueso et al. 2001, Naef & Woodside 2007, Brunton & Russell 2008). The development of hyperleptinemia and leptin resistance during pregnancy has been proposed to be a compensatory mechanism to allow for increased appetite and food intake to meet the energy needs of the developing fetus (Brunton & Russell 2008).

Leptin may also have important roles in the placenta, including nutrient delivery to the fetus, angiogenesis and vascular smooth muscle growth in chorionic villi, and immune modulation (Jansson et al. 2003, White et al. 2006, Bohlen et al. 2007, Garonna et al. 2011, Tessier et al. 2013). Although central leptin resistance appears to be physiologic in healthy pregnant women, obese pregnant women who have even higher concentrations of leptin appear to also have placental resistance that may be pathologic (Farley et al. 2010, Tessier et al. 2013). Higher degrees of maternal hyperleptinemia in obesity are associated with downregulation of leptin receptors in the placenta (Farley et al. 2010) and increased concentrations of the soluble form of leptin receptors that may prevent leptin binding and signaling (Challier et al. 2003). These disturbances in leptin physiology have been linked to gestational diabetes mellitus, fetal growth restriction, macrosomia, and preeclampsia, but the mechanisms of pathophysiology remains to be elucidated (Acromite et al. 2004, Tessier et al. 2013).

States of leptin deficiency

Hypoleptinemia is extremely rarely congenital. In these patients, the lack of leptin activity results in a drive to consume food and conservation of energy expenditure that does not feed back to the hypothalamus. Acquired relative hypoleptinemia is much more common, particularly seen in women with HA or anorexia nervosa. In these patients, hypoleptinemia reflects a state of chronic energy deficiency and leads to compensatory mechanisms. These mechanisms include hypogonadotropic hypogonadism, euthyroid sick syndrome, and other neuroendocrine abnormalities as well as deficits in bone metabolism and immune function (Chan et al. 2003, Chan & Mantzoros 2005, Dardeno et al. 2010).

Congenital leptin deficiency

Patients with complete leptin deficiency due to homozygous leptin gene mutations develop extreme obesity with hyperphagia, insulin resistance, and distinct neuroendocrine abnormalities, including hypogonadism (Farooqi et al. 2002, Licinio et al. 2004). Ozata et al. (1999) reported three adult patients, all of whom had delayed puberty and hypothalamic hypogonadism. The male patient had not entered puberty by the age of 23, with no facial hair, scant pubic and axillary hair, small penis and testes, and azospermia. His total testosterone concentration was 80 ng/ml (normal range: 241–827) with inappropriately normal gonadotropin concentrations. One of the female patients developed scanty menstrual bleeding every 7–8 months at the age of 29, while the other female patient started regular menses at age of 35 though their cycles were found to have a luteal-phase defect. Ultrasonography of mammary gland had shown minimal to no glandular tissue for both women. Hypogonadism appeared to be due to a defect at the hypothalamic level as these patients had normal gonadotropin responses to GnRH stimulation (Ozata et al. 1999). Leptin treatment stimulated the onset of puberty in the male patient who then developed increased facial hair, acne, pubic and axillary hair, increased size of penis and testes, and normal ejaculatory patterns (Licinio et al. 2004). Furthermore, he reported improvements in muscle strength and well-being. The female patients developed regular menses with elevated mid-luteal phase progesterone concentrations indicating ovulation. After 6 months of leptin treatment, 24-h average concentrations of LH significantly increased from baseline, attributed to increased pulse amplitudes and not pulse frequency.

Results in children and adolescents confirm leptin's role as a permissive factor in puberty. Treatment with leptin did not affect the prepubertal pattern of gonadotropin secretion in younger patients, but did initiate puberty in a child who was previously prepubertal despite a bone age of 12.5 years (Farooqi et al. 2002). Another case report describes a girl whose pubertal development had arrested at Tanner stage 3 (von Schnurbein et al. 2012). Before initiation of leptin therapy, LH and FSH were at prepubertal concentrations without any nocturnal pulsatility, and response to GnRH stimulation was low. After 11 weeks of therapy, basal and stimulated LH and FSH concentrations rose to pubertal concentrations and nocturnal pulsatility was restored; weight had not yet begun to fall at this time. Menarche occurred 76 weeks after initiation of treatment.

Lipodystrophy

Similar to patients with congenital leptin deficiency, patients with lipodystrophy, either due to a congenital or an acquired destruction of adipose tissue, are also hypoleptinemic and insulin resistant (Pardini et al. 1998, Nagy et al. 2003, Fiorenza et al. 2011). In addition to improving insulin resistance (Lee et al. 2006, Ebihara et al. 2007, Brennan et al. 2009, Magkos et al. 2011), leptin may also have beneficial effects on reproductive function of lipodystrophic women (Musso et al. 2005). Women with lipodystrophy usually have enlarged polycystic ovaries, hyperandrogenism, amenorrhea, and infertility (Pardini et al. 1998, Musso et al. 2005). In an open-label study of 10 women with generalized lipodystrophy, leptin treatment for 12 months decreased serum free testosterone concentrations by 50%, increased sex hormone-binding globulin (SHBG) concentrations, and increased the LH response to GnRH (Musso et al. 2005). SHBG is a sex steroid transport protein that decreases circulating concentrations of free testosterone, and low concentrations of SHBG have been associated with metabolic syndrome and type 2 diabetes (Brand et al. 2011). Eight of these women were amenorrheic before therapy, and leptin treatment induced normal menses in all these women (Musso et al. 2005). These improvements were likely due to both a direct effect of leptin on the reproductive system and an indirect effect through weight loss and increased insulin sensitivity. In contrast, the men with lipodystrophy had normal concentrations of testosterone, which increased with leptin treatment; LH response to GnRH was not affected (Musso et al. 2005).

Despite the low concentrations of leptin in these lipodystrophic patients, puberty does not seem to be affected. Musso et al. (2005) followed eight male patients from early childhood, and all underwent appropriate pubertal development unrelated to leptin therapy. Andreelli et al. (2000) described two female patients with Seip-Berardinelli syndrome, a form of generalized lipoatrophy starting in early infancy. Both patients underwent menarche between 11 and 12 years of age and had regular menses; one had become pregnant to term three times. Thus, very low concentrations of leptin may be sufficient to allow for progression through puberty in these patients.

Hypothalamic amenorrhea

More than 30% of cases of amenorrhea in women of reproductive age are attributed to HA (Reindollar et al. 1986). Given the prevalence of this condition, the relationship between HA and leptin has been well-studied.

Compared with weight-matched (Miller et al. 1998, Andrico et al. 2002) and activity-matched (Thong et al. 2000, Corr et al. 2011) eumenorrheic controls, women with HA have lower leptin concentrations. Leptin concentrations also significantly increase in association with recovery from HA and anorexia nervosa (Misra et al. 2004, Dei et al. 2008, Kostrzewa et al. 2013).

By signaling a state of energy deficiency, hypoleptinemia has been found to be a key mediator of neuroendocrine abnormalities seen in HA (Chan & Mantzoros 2005, Khan et al. 2012). In addition to dysfunctional HPG axis resulting in anovulation and estrogen deficiency to prevent pregnancy, other neuroendocrine axes are affected to serve as an adaptive response to negative energy balance. These effects include increased concentrations of corticotropin-releasing hormone, adrenocorticotropic hormone (ACTH), and cortisol (Laughlin & Yen 1997, Genazzani et al. 2001, Gordon 2010); low to normal concentrations of thyrotropin, decreased concentrations of thyroid hormone, and increased concentrations of the inactive reverse triiodothyronine (Warren et al. 1999, Genazzani et al. 2006, Bomba et al. 2007); and growth hormone (GH) resistance with elevated concentrations of GH (Berga et al. 1989, Laughlin & Yen 1996, Laughlin et al. 1998) but decreased insulin-like growth factor 1 (IGF1) activity (Laughlin & Yen 1996, Genazzani et al. 1996, Chan et al. 2008). Two pivotal clinical trials have demonstrated how leptin treatment in physiological doses can restore normal neuroendocrine physiology as well as improve bone metabolism and immune function parameters. One is a proof-of-concept pilot study of 3 month duration (Welt et al. 2004), while the other is a randomized, placebo-controlled trial of 9 month duration (Chou et al. 2011).

In these two clinical trials, leptin replacement restored the HPG axis in hypothalamic amenorrhic women (Welt et al. 2004, Chou et al. 2011). Leptin treatment significantly increased LH concentrations, LH pulse frequency (but not amplitude), and estradiol and progesterone concentrations. In the open-label trial, pelvic ultrasonography documented increases in ovarian volume during the follicular phase and thicker endometrium after treatment (Welt et al. 2004). Significant increases in the number of dominant follicles and maximal follicular diameter were also observed. Five out of eight treated women developed menses, three of which were ovulatory. In the follow-up randomized controlled trial of 36 weeks duration, seven of ten participants receiving leptin therapy developed menses, compared with two of nine participants on placebo (P=0.0046; Chou et al. 2011). Four of the menstruating participants on leptin were determined to be ovulatory based on elevated serum progesterone concentrations during the mid-luteal phase. Of the five treated participants who regained menses and completed the study, three continued to have menses 16 weeks after discontinuation of leptin. One women became pregnant at 24 weeks. The improvements in reproductive function in these treated women were not due to changes in physical activity level, weight gain, or increase in fat mass. By signaling adequate energy stores, leptin seems to permit the return of reproductive function in HA, similar to its permissive role in the initiation of puberty (Licinio et al. 2004, Chan & Mantzoros 2005). Leptin treatment was also found to decrease cortisol concentrations, increase thyroid hormone concentrations, and tended to increase IGF1 concentrations (Welt et al. 2004, Chou et al. 2011).

In addition to its neuroendocrine effects, treatment with leptin, either directly and/or via normalization of neuroendocrine hormones, improves bone health. After a treatment duration of 2 years, lumbar bone mineral content and bone mineral density increased significantly from baseline by 6 and 4% respectively (Sienkiewicz et al. 2011). Albeit no direct comparison studies are available, this effect appears to be better than that of estrogen therapy, the use of which has been controversial (Ducher et al. 2011). In one of the largest randomized controlled trials, 2 years of oral contraceptives in oligo/amenorrheic runners resulted in a 1% gain in spine bone mineral density per year, which was similar to runners who regained periods spontaneously but significantly greater than those who remained oligo/amenorrheic (Cobb et al. 2007). Estrogen may have limited effects in amenorrheic athletes as it has primarily anti-resorptive effects on bone, and the markers of bone turnover in these women are already low (Ducher et al. 2011). Furthermore, estrogen therapy, unlike leptin replacement, does not address the disturbances in thyroid hormone, IGF1, and cortisol concentrations. Likewise, recombinant human IGF1 (Grinspoon et al. 2002) and androgens (Gordon et al. 1999) have been found to have modest responses in bone metabolism in women with anorexia nervosa, and a lesser response would be suspected in women with the less severe condition of HA.

Finally, leptin treatment has been shown to improve deficiencies in the immune system (Chan et al. 2005, Matarese et al. 2013). The women with HA in the randomized controlled trial were found to have reduced total number of lymphocytes, B cells, and natural killer cells, and leptin restored their total lymphocyte count with increases in CD4+ and CD8+ T-cell counts (Matarese et al. 2013). In contrast, the placebo-treated HA subjects experienced a decreasing trend in lymphocyte count to frank lymphopenia over time. Women with HA were also found to have reduced T-cell proliferative capacity, compared with normoleptinemic control women, and this was partially restored with leptin. In this small study, these effects of leptin were not associated with changes in serum hormone concentrations of cortisol, ACTH, or insulin; circulating cytokines (e.g., IL1, IL7, or IL15); or metabolic/inflammatory parameters (e.g., CD40–CD40 ligand, soluble TNF receptors, monocyte chemoattractant protein 1, myeloperoxidase, and C-reactive protein). In peripheral bone marrow cells, leptin treatment was found to upregulate genes involved in lymphocyte survival, proliferation, and migration (e.g., IL7, neurotrophin-3, ADAM-metallopeptidase 23 (ADAM23), and vascular adhesion molecule 1 (VCAM1)) and downregulate genes involved in apoptosis (e.g., B-cell chronic lymphocytic leukemia/lymphoma 10 (BCL10) and TP53-regulator of apoptosis 1 (TRIAP1)) (Matarese et al. 2013).

As expected, women treated with leptin lost weight and fat mass. With careful monitoring and dose adjustments, however, weight can be maintained and loss of total body fat mass and percentage can be minimized on leptin therapy. In the placebo-controlled trial of leptin in women with HA, treatment dose was decreased if the participant lost >5% of her baseline weight (Chou et al. 2011). As a result, BMI did not change in the leptin group (20.8±0.6 kg/m2 at week 36 compared with 21.1±0.6 kg/m2 at baseline) compared with the placebo group (19.6±0.4 kg/m2 at week 36 compared with 19.8±0.7 kg/m2 at baseline; P=0.23). However, the leptin group did experience a progressive loss of total body fat mass and percentage with a mean loss of 2 kg of fat. The loss of fat was noted from both peripheral and central areas of distributions and reverted 16 weeks after discontinuation of leptin. Lean body mass was not affected (Brinkoetter et al. 2011). No changes in resting energy expenditure (measured by indirect calorimetric testing) or food intake (measured by 3-day food diaries) were noted, though the methods are not sensitive (Chou et al. 2011).

Type 1 diabetes

An interest for the use of leptin in patients with type 1 diabetes has recently emerged, though clinical studies are lacking. Many patients with type 1 diabetes have low concentrations of leptin (Kiess et al. 1998), possibly due to suppression by elevated circulating concentrations of free fatty acids and ketones from lipolysis seen in the state of insulin deficiency (Moon et al. 2013). In essence, uncontrolled type 1 diabetes represents a state of energy deficiency in that there is an inability to utilize available energy. Although not yet shown in humans, leptin treatment has been shown to improve glucose control as well as glucose variability via suppression of glucagon in rodent studies (Wang et al. 2010).

Before the use of insulin, type 1 diabetes patients experienced severe hypogonadism and low fertility rates, and although this improved with the introduction of insulin, inadequate control is still associated with hypogonadotropic hypogonadism with amenorrhea and delayed puberty (Codner et al. 2012). Both insulin deficiency and hyperglycemia have been found to disrupt the metabolic control of the HPG axis from the hypothalamus to the ovary (Codner et al. 2012). Leptin deficiency may also be contributing to hypogonadism in uncontrolled type 1 diabetes. In streptozotocin-induced diabetic rats, central infusion of leptin, but not insulin, restored hypothalamic Kiss1 gene expression and normalized LH and sex steroid concentrations (Castellano et al. 2006). Again, leptin treatment has not been studied in this context in humans, and glucose control would be the primary focus of treatment and this alone may improve reproductive function.

States of leptin excess

Obese individuals have an increased risk of hypogonadism and subfecundity (Ramlau-Hansen et al. 2007). Multiple factors adversely affecting reproduction function in obesity include increased inflammatory markers, increased concentrations of free fatty acids, hyperinsulinemia and insulin resistance, low concentrations of SHBG, and high concentrations of free androgens in women, all of which are often related to concentrations of adipokines, such as adiponectin, resistin, visfatin, and leptin (Jungheim et al. 2012, Chen et al. 2013).

Focusing on leptin, most obese individuals do not have congenital leptin deficiency and have high serum leptin concentrations (Considine et al. 1996) mainly due to diet-induced expansion of adipocytes (Moon et al. 2013). Despite hyperleptinemia, these patients are felt to be tolerant or resistant to the effects of leptin (Moon et al. 2011), and treatment with leptin in obese adults results in modest to no weight loss (Heymsfield et al. 1999, Moon et al. 2011). Based on in vitro and rodent studies, several mechanisms of leptin resistance have been proposed, including impaired transport across the blood brain barrier (El-Haschimi et al. 2000), impaired leptin signaling by suppressor of cytokine signaling 3 (SOCS3; Bjorbaek et al. 1998, Dunn et al. 2005), impaired leptin receptor trafficking (Bjornholm et al. 2007, Morrison et al. 2007), saturation of leptin signaling pathways (Moon et al. 2012), endoplasmic reticulum stress (Ozcan et al. 2009), and downmodulation of leptin's neural circuitry (Pinto et al. 2004, Moon et al. 2013). A few of these mechanisms have been confirmed in human studies (Moon et al. 2011). In human adipose tissue and peripheral blood mononuclear cells, leptin signaling pathways have been confirmed to saturate near a concentration of 50 ng/ml and STAT3 signaling has been found to be inhibited by endoplasmic reticulum stress (Moon et al. 2011).

Central leptin resistance has been proposed as a mechanism for hypogonadotropic hypogonadism related to obesity (Teerds et al. 2011). This idea has been explored by Tortoriello et al. (2004) in a strain of diet-induced obese female mice with subsequent leptin resistance. High-fat diet was associated with more than a 60% decrease in natural pregnancy rates. Normal ovulatory response and pregnancy rates were achieved after exogenous gonadotropin stimulation, suggesting a hypothalamic defect. Indeed, PCR quantification of hypothalamic cDNA revealed a 100% upregulation of NPY and 50% suppression of GnRH compared with lean counterparts. Furthermore, there was 95% reduction in leptin receptor type B expression but no change in SOCS3 expression, suggesting the importance of decreased receptor availability in leptin resistance. Interestingly, fertility of male rats was not affected despite developing a similar degree of obesity and hyperleptinemia. The authors reason that this sexual dimorphism makes teleological sense as females require much greater investment in the reproductive process than males. However, these effects were only observed in this particular strain of female mice and not in a second strain. There may be other factors, including genetic, that make certain individuals predisposed to the adverse reproductive effects of central leptin resistance.

In addition to central effects, hyperleptinemia has also been found to directly affect gonadal tissue in both genders. To represent both genders, the effects of hyperleptinemia related to obesity will be further discussed in women with PCOS and men with type 2 diabetes mellitus.

Polycystic ovarian syndrome

Studies have been conflicting on whether women with PCOS have higher or similar concentrations of leptin compared with weight-matched controls, but, as expected, leptin concentrations correlate strongly with BMI in both groups (Brzechffa et al. 1996, Laughlin et al. 1997, Mantzoros et al. 1997b, Kowalska et al. 2001, Yildizhan et al. 2011). Women with PCOS may actually have higher free concentrations of leptin. Hahn et al. (2006) have found lower concentrations of soluble leptin receptors and have proposed this to be a mechanism to compensate for leptin resistance.

Leptin, however, does not appear to play a major role in HPG axis dysfunction or hyperandrogenemia. Leptin concentrations do not seem to correlate with concentrations of LH, testosterone, dehydroepiandrosterone sulfate, and estradiol (Brzechffa et al. 1996, Mantzoros et al. 1997b, Kowalska et al. 2001). Pulses of leptin have been found to synchronized with pulses of LH in patients with PCOS, as they are in regularly menstruating women (Sir-Petermann et al. 1999). However, the significance of this is unclear (Sir-Petermann et al. 1999). Leptin concentrations are negatively associated with SHBG and free concentrations of sex steroids (Laughlin et al. 1997, Hahn et al. 2006), although this may be related to the negative effect of insulin resistance on SHBG concentrations.

Although hyperleptinemia may not play a large role in the central dysfunction of PCOS women due to central leptin resistance, it may interfere with follicular development. Leptin receptors have been detected in granulosa and theca cells of human ovarian follicles (Cioffi et al. 1996, Agarwal et al. 1999). In an in vitro study, leptin has been shown to stimulate granulosa cells to secrete estradiol and progesterone at low concentrations but inhibit secretion at high concentrations (Karamouti et al. 2009). Leptin has also been found, in a dose-dependent manner, to inhibit IGFI augmentation of FSH-stimulated estradiol production by granulosa cells and LH-stimulated androgen production by theca cells, thus decreasing the substrate for estradiol (Agarwal et al. 1999). Clinically, however, no significant differences in serum leptin concentrations between ovulatory and anovulatory PCOS subjects have been found, therefore any role of leptin on follicular development may be mediated through differences in tissue sensitivity (Pirwany et al. 2001, Carmina et al. 2009).

Women with PCOS are also found to have lower rates of fertilization, implantation, and pregnancy per in vitro fertilization cycle, compared with infertile women with tubal blockage (Li et al. 2007). Fertile women with PCOS have lower concentrations of serum and follicular fluid leptin than infertile women with PCOS, adjusted for age and BMI (Mantzoros et al. 2000, Li et al. 2007). High concentrations of leptin in serum and follicular fluid were associated with downregulation of STAT3 phosphorylation in granulosa cells despite no change in leptin receptor or SCOS3 expression, and this may contribute to infertility in PCOS (Li et al. 2007).

Hyperinsulinemia and insulin resistance are also features of PCOS. Studies show that leptin concentrations do correlate with homeostasis model assessment insulin resistance index as well as triglyceride concentrations (Hahn et al. 2006, Pehlivanov & Mitkov 2009, Yildizhan et al. 2011). The interactions between leptin and insulin signaling pathways prove to be complex, with leptin differentially modifying the metabolic effects of leptin. While leptin stimulates some effects of insulin, such as increasing glucose uptake in skeletal muscle and inhibiting hepatic glucose output, it also antagonizes other effects of insulin, such as the downregulation of phosphoenolpyruvate carboxykinase (PEPCK) expression and stimulation of insulin receptor substrate 1 (IRS1) phosphorylation and associated PI3K activity in hepatocytes (Moon et al. 2013). Furthermore, leptin and insulin may share mechanisms of resistance, specifically SOCS3 (Moon et al. 2013). This combination of leptin and insulin resistance may be important in the development of PCOS. Hill et al. (2010) have shown that deleting both leptin and insulin receptors in POMC neurons in female mice resulted in increased weight, insulin resistance, elevated testosterone concentrations, elevated LH concentrations, more degenerating ovarian follicles, and reduced fertility, all characteristics associated with PCOS. Deleting either the insulin or leptin receptor did not result in reduced fertility (Hill et al. 2010). However, obesity and insulin resistance are likely not the causes of PCOS in humans as some women with PCOS are lean and sensitive to insulin. It has been proposed that obesity and insulin resistance may amplify rather than cause the reproductive features of PCOS (Walters et al. 2012). In clinical trials treatment with insulin sensitizing medications, such as thiazolidinediones and metformin, did not seem to consistently lower leptin concentrations unless there was weight loss (Mantzoros et al. 1997b, Belli et al. 2004, Romualdi et al. 2008, Tfayli et al. 2011), further indicating the complexity of the insulin and leptin interplay.

To date no interventional trials to investigate the effect of leptin on the HPG axis, androgen concentrations, and metabolic parameters in women with PCOS have been performed. Given the high concentrations of leptin and its resistance, it is unlikely that the administration of leptin will provide the beneficial effects seen in the patients with lipodystrophy, hypoleptinemia, and PCOS features.

Diabetes mellitus type 2

At least 25% of men with type 2 diabetes have hypogonadotropic hypogonadism, and pathophysiological mechanisms may include insulin resistance and inflammation at the hypothalamus suppressing GnRH secretion (Dandona & Dhindsa 2011). Hyperleptinemia and central leptin resistance may also play a role. Leptin concentrations have been found to inversely correlate with testosterone concentrations, even after controlling for SHBG and estradiol, and leptin concentrations were the best hormonal predictor of low androgen concentrations in obesity (Isidori et al. 1999).

In addition to the effects of central leptin resistance, hyperleptinemia may also affect the HPG axis at the level of the testes. Leydig cells in rats and humans express leptin receptors, and in vitro studies in rats have demonstrated that leptin inhibits hCG-stimulated testosterone production by Leydig cells and testicular tissue (Banks et al. 1999, Caprio et al. 1999, Tena-Sempere et al. 1999, Aquila et al. 2005). In humans, hCG-induced testosterone production capacity has been found to be inversely related to serum leptin concentrations (Isidori et al. 1999). In addition, human spermatozoa also express leptin (Soyupek et al. 2005), which may act upon Leydig cells in a paracrine manner. In contrast to the blood–brain barrier, leptin transport across the blood–testis barrier does not seem to be limited by saturation (Banks et al. 1999).

In contrast to type 1 diabetes, clinical trials of leptin on type 2 diabetes have been carried out. Leptin has been shown to be largely ineffective in improving insulin resistance in obese subjects with type 2 diabetes (Mittendorfer et al. 2011, Moon et al. 2011). Presumably, additional exogenous leptin would also not affect the HPG axis.

Conclusion

In summary, leptin provides the brain metabolic information to determine whether the body's energy stores are sufficient for reproduction. Clinical trials have shown that hypoleptinemia contributes to the pathology of HA, a state of chronic energy deficiency, and replacement with recombinant human leptin may serve as treatment option in select patients in the future. The role of leptin in states of energy excess, such as obesity, PCOS, and type 2 diabetes, is less clear but likely related to leptin resistance, and treatment to improve metabolic as well as reproductive parameters may require medications that promote leptin sensitivity. Given the prevalence of obesity, more research, from basic to translational to clinical, is warranted to further explore this possibility.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. C Mantzoros has served as a consultant to AstraZeneca.

Funding

This review did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

References

  • AcromiteMZiotopoulouMOrlovaCMantzorosC2004Increased leptin levels in preeclampsia: associations with BMI, estrogen and SHBG levels. Hormones34652. (doi:10.14310/horm.2002.11111)

  • AgarwalSKVogelKWeitsmanSRMagoffinDA1999Leptin antagonizes the insulin-like growth factor-I augmentation of steroidogenesis in granulosa and theca cells of the human ovary. Journal of Clinical Endocrinology and Metabolism8410721076. (doi:10.1210/jcem.84.3.5543)

  • AmstaldenMGarciaMRStankoRLNizielskiSEMorrisonCDKeislerDHWilliamsGL2002Central infusion of recombinant ovine leptin normalizes plasma insulin and stimulates a novel hypersecretion of luteinizing hormone after short-term fasting in mature beef cows. Biological Reproduction6615551561. (doi:10.1095/biolreprod66.5.1555)

  • AndreelliFHanaire-BroutinHLavilleMTauberJPRiouJPThivoletC2000Normal reproductive function in leptin-deficient patients with lipoatropic diabetes. Journal of Clinical Endocrinology and Metabolism85715719. (doi:10.1210/jcem.85.2.6392)

  • AndricoSGamberaASpecchiaCPellegriniCFalsettiLSartoriE2002Leptin in functional hypothalamic amenorrhoea. Human Reproduction1720432048. (doi:10.1093/humrep/17.8.2043)

  • AquilaSGentileMMiddeaECatalanoSMorelliCPezziVAndoS2005Leptin secretion by human ejaculated spermatozoa. Journal of Clinical Endocrinology and Metabolism9047534761. (doi:10.1210/jc.2004-2233)

  • BackholerKSmithJTRaoAPereiraAIqbalJOgawaSLiQClarkeIJ2010Kisspeptin cells in the ewe brain respond to leptin and communicate with neuropeptide Y and proopiomelanocortin cells. Endocrinology15122332243. (doi:10.1210/en.2009-1190)

  • BanksWAMcLayRNKastinAJSarmientoUScullyS1999Passage of leptin across the blood-testis barrier. American Journal of Physiology276E1099E1104.

  • BatesSHStearnsWHDundonTASchubertMTsoAWWangYBanksASLaveryHJHaqAKMaratos-FlierE2003STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature421856859. (doi:10.1038/nature01388)

  • BelliSHGraffignaMNOnetoAOteroPSchurmanLLevalleOA2004Effect of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome. Fertility and Sterility81624629. (doi:10.1016/j.fertnstert.2003.08.024)

  • BergaSLMortolaJFGirtonLSuhBLaughlinGPhamPYenSS1989Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. Journal of Clinical Endocrinology and Metabolism68301308. (doi:10.1210/jcem-68-2-301)

  • BjorbaekCElmquistJKFrantzJDShoelsonSEFlierJS1998Identification of SOCS-3 as a potential mediator of central leptin resistance. Molecular Cell1619625. (doi:10.1016/S1097-2765(00)80062-3)

  • BjornholmMMunzbergHLeshanRLVillanuevaECBatesSHLouisGWJonesJCIshida-TakahashiRBjorbaekCMyersMGJr2007Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function. Journal of Clinical Investigation11713541360. (doi:10.1172/JCI30688)

  • BluherSMantzorosCS2007Leptin in reproduction. Current Opinion in Endocrinology Diabetes and Obesity14458464. (doi:10.1097/MED.0b013e3282f1cfdc)

  • BohlenFKratzschJMuellerMSeidelBFriedman-EinatMWitzigmannHTeupserDKoernerAStorckMThieryJ2007Leptin inhibits cell growth of human vascular smooth muscle cells. Vascular Pharmacology466771. (doi:10.1016/j.vph.2006.06.014)

  • BombaMGamberaABoniniLPeroniMNeriFScagliolaPNacinovichR2007Endocrine profiles and neuropsychologic correlates of functional hypothalamic amenorrhea in adolescents. Fertility and Sterility87876885. (doi:10.1016/j.fertnstert.2006.09.011)

  • BrandJSvan der TweelIGrobbeeDEEmmelot-VonkMHvan der SchouwYT2011Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies. International Journal of Epidemiology40189207. (doi:10.1093/ije/dyq158)

  • BrennanAMLeeJHTsiodrasSChanJLDoweikoJChimientiSNWadhwaSGKarchmerAWMantzorosCS2009r-metHuLeptin improves highly active antiretroviral therapy-induced lipoatrophy and the metabolic syndrome, but not through altering circulating IGF and IGF-binding protein levels: observational and interventional studies in humans. European Journal of Endocrinology160173176. (doi:10.1530/EJE-08-0597)

  • BrinkoetterMMagkosFVamviniMMantzorosCS2011Leptin treatment reduces body fat but does not affect lean body mass or the myostatin–follistatin–activin axis in lean hypoleptinemic women. American Journal of Physiology. Endocrinology and Metabolism301E99E104. (doi:10.1152/ajpendo.00146.2011)

  • BruntonPJRussellJA2008The expectant brain: adapting for motherhood. Nature Reviews. Neuroscience91125. (doi:10.1038/nrn2280)

  • BrzechffaPRJakimiukAJAgarwalSKWeitsmanSRBuyalosRPMagoffinDA1996Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism8141664169. (doi:10.1210/jcem.81.11.8923878)

  • CaprioMIsidoriAMCartaARMorettiCDufauMLFabbriA1999Expression of functional leptin receptors in rodent Leydig cells. Endocrinology14049394947. (doi:10.1210/endo.140.11.7088)

  • CarminaEBucchieriSMansuetoPRiniGFerinMLoboRA2009Circulating levels of adipose products and differences in fat distribution in the ovulatory and anovulatory phenotypes of polycystic ovary syndrome. Fertility and Sterility9113321335. (doi:10.1016/j.fertnstert.2008.03.007)

  • CastellanoJMNavarroVMFernandez-FernandezRRoaJVigoEPinedaRDieguezCAguilarEPinillaLTena-SempereM2006Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats. Diabetes5526022610. (doi:10.2337/db05-1584)

  • ChallierJGaltierMBinteinTCortezALepercqJHauguel-de MouzonS2003Placental leptin receptor isoforms in normal and pathological pregnancies. Placenta249299. (doi:10.1053/plac.2002.0805)

  • ChanJLMantzorosCS2005Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet3667485. (doi:10.1016/S0140-6736(05)66830-4)

  • ChanJLHeistKDePaoliAMVeldhuisJDMantzorosCS2003The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. Journal of Clinical Investigation11114091421. (doi:10.1172/JCI200317490)

  • ChanJLBullenJStoynevaVDepaoliAMAddyCMantzorosCS2005Recombinant methionyl human leptin administration to achieve high physiologic or pharmacologic leptin levels does not alter circulating inflammatory marker levels in humans with leptin sufficiency or excess. Journal of Clinical Endocrinology and Metabolism9016181624. (doi:10.1210/jc.2004-1921)

  • ChanJLWilliamsCJRacitiPBlakemanJKelesidisTKelesidisIJohnsonMLThornerMOMantzorosCS2008Leptin does not mediate short-term fasting-induced changes in growth hormone pulsatility but increases IGF-I in leptin deficiency states. Journal of Clinical Endocrinology and Metabolism9328192827. (doi:10.1210/jc.2008-0056)

  • ChardonnensDCameoPAubertMLPralongFPIslamiDCampanaAGaillardRCBischofP1999Modulation of human cytotrophoblastic leptin secretion by interleukin-1α and 17β-oestradiol and its effect on HCG secretion. Molecular Human Reproduction510771082. (doi:10.1093/molehr/5.11.1077)

  • ChenXJiaXQiaoJGuanYKangJ2013Adipokines in reproductive function: a link between obesity and polycystic ovary syndrome. Journal of Molecular Endocrinology50R21R37. (doi:10.1530/JME-12-0247)

  • ChouSHChamberlandJPLiuXMatareseGGaoCStefanakisRBrinkoetterMTGongHArampatziKMantzorosCS2011Leptin is an effective treatment for hypothalamic amenorrhea. PNAS10865856590. (doi:10.1073/pnas.1015674108)

  • CioffiJAShaferAWZupancicTJSmith-GburJMikhailAPlatikaDSnodgrassHR1996Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction. Nature Medicine2585589. (doi:10.1038/nm0596-585)

  • CobbKLBachrachLKSowersMNievesJGreendaleGAKentKKBrownBWJrPettitKHarperDMKelseyJL2007The effect of oral contraceptives on bone mass and stress fractures in female runners. Medicine and Science in Sports and Exercise3914641473. (doi:10.1249/mss.0b013e318074e532)

  • CodnerEMerinoPMTena-SempereM2012Female reproduction and type 1 diabetes: from mechanisms to clinical findings. Human Reproduction Update18568585. (doi:10.1093/humupd/dms024)

  • ConsidineRVSinhaMKHeimanMLKriauciunasAStephensTWNyceMROhannesianJPMarcoCCMcKeeLJBauerTL1996Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New England Journal of Medicine334292295. (doi:10.1056/NEJM199602013340503)

  • CorrMDe SouzaMJToombsRJWilliamsNI2011Circulating leptin concentrations do not distinguish menstrual status in exercising women. Human Reproduction26685694. (doi:10.1093/humrep/deq375)

  • CowleyMASmartJLRubinsteinMCerdanMGDianoSHorvathTLConeRDLowMJ2001Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature411480484. (doi:10.1038/35078085)

  • CravoRMFrazaoRPerelloMOsborne-LawrenceSWilliamsKWZigmanJMViannaCEliasCF2013Leptin signaling in Kiss1 neurons arises after pubertal development. PLoS ONE8e58698. (doi:10.1371/journal.pone.0058698)

  • DandonaPDhindsaS2011Update: hypogonadotropic hypogonadism in type 2 diabetes and obesity. Journal of Clinical Endocrinology and Metabolism9626432651. (doi:10.1210/jc.2010-2724)

  • DardenoTAChouSHMoonHSChamberlandJPFiorenzaCGMantzorosCS2010Leptin in human physiology and therapeutics. Frontiers in Neuroendocrinology31377393. (doi:10.1016/j.yfrne.2010.06.002)

  • DeiMSeravalliVBruniVBalziDPasquaA2008Predictors of recovery of ovarian function after weight gain in subjects with amenorrhea related to restrictive eating disorders. Gynecological Endocrinology24459464. (doi:10.1080/09513590802246141)

  • DonatoJJrCravoRMFrazaoRGautronLScottMMLacheyJCastroIAMargathoLOLeeSLeeC2011Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. Journal of Clinical Investigation121355368. (doi:10.1172/JCI45106)

  • DucherGTurnerAIKukuljanSPantanoKJCarlsonJLWilliamsNIDe SouzaMJ2011Obstacles in the optimization of bone health outcomes in the female athlete triad. Sports Medicine41587607. (doi:10.2165/11588770-000000000-00000)

  • DunnSLBjornholmMBatesSHChenZSeifertMMyersMGJr2005Feedback inhibition of leptin receptor/Jak2 signaling via Tyr1138 of the leptin receptor and suppressor of cytokine signaling 3. Molecular Endocrinology19925938. (doi:10.1210/me.2004-0353)

  • EbiharaKKusakabeTHirataMMasuzakiHMiyanagaFKobayashiNTanakaTChushoHMiyazawaTHayashiT2007Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. Journal of Clinical Endocrinology and Metabolism92532541. (doi:10.1210/jc.2006-1546)

  • El-HaschimiKPierrozDDHilemanSMBjorbaekCFlierJS2000Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. Journal of Clinical Investigation10518271832. (doi:10.1172/JCI9842)

  • EliasCF2012Leptin action in pubertal development: recent advances and unanswered questions. Trends in Endocrinology and Metabolism23915. (doi:10.1016/j.tem.2011.09.002)

  • EliasCFPurohitD2013Leptin signaling and circuits in puberty and fertility. Cellular and Molecular Life Sciences70841862. (doi:10.1007/s00018-012-1095-1)

  • FarleyDMChoiJDudleyDJLiCJenkinsSLMyattLNathanielszPW2010Placental amino acid transport and placental leptin resistance in pregnancies complicated by maternal obesity. Placenta31718724. (doi:10.1016/j.placenta.2010.06.006)

  • FarooqiISMatareseGLordGMKeoghJMLawrenceEAgwuCSannaVJebbSAPernaFFontanaS2002Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. Journal of Clinical Investigation11010931103. (doi:10.1172/JCI0215693)

  • FiorenzaCGChouSHMantzorosCS2011Lipodystrophy: pathophysiology and advances in treatment. Nature Reviews. Endocrinology7137150. (doi:10.1038/nrendo.2010.199)

  • FrischREMcArthurJW1974Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science185949951. (doi:10.1126/science.185.4155.949)

  • Garcia-MayorRVAndradeMARiosMLageMDieguezCCasanuevaFF1997Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary–gonadal hormones, and pubertal stage. Journal of Clinical Endocrinology and Metabolism8228492855. (doi:10.1210/jcem.82.9.4235)

  • GaronnaEBothamKMBirdseyGMRandiAMGonzalez-PerezRRWheeler-JonesCP2011Vascular endothelial growth factor receptor-2 couples cyclo-oxygenase-2 with pro-angiogenic actions of leptin on human endothelial cells. PLoS ONE6e18823. (doi:10.1371/journal.pone.0018823)

  • GenazzaniADPetragliaFGastaldiMGambaOCorazzaFD'AmbrogioGGenazzaniAR1996Growth hormone (GH)-releasing hormone-induced GH response in hypothalamic amenorrhea: evidence of altered central neuromodulation. Fertility and Sterility65935938.

  • GenazzaniADBersiCLuisiSFruzzettiFMalavasiBLuisiMPetragliaFGenazzaniAR2001Increased adrenal steroid secretion in response to CRF in women with hypothalamic amenorrhea. Journal of Steroid Biochemistry and Molecular Biology78247252. (doi:10.1016/S0960-0760(01)00094-2)

  • GenazzaniADRicchieriFLanzoniCStrucchiCJasonniVM2006Diagnostic and therapeutic approach to hypothalamic amenorrhea. Annals of the New York Academy of Sciences1092103113. (doi:10.1196/annals.1365.009)

  • GordonCM2010Clinical practice. Functional hypothalamic amenorrhea. New England Journal of Medicine363365371. (doi:10.1056/NEJMcp0912024)

  • GordonCMGraceEEmansSJGoodmanECrawfordMHLeboffMS1999Changes in bone turnover markers and menstrual function after short-term oral DHEA in young women with anorexia nervosa. Journal of Bone and Mineral Research14136145. (doi:10.1359/jbmr.1999.14.1.136)

  • GrinspoonSThomasLMillerKHerzogDKlibanskiA2002Effects of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa. Journal of Clinical Endocrinology and Metabolism8728832891. (doi:10.1210/jcem.87.6.8574)

  • GruesoERochaMPuertaM2001Plasma and cerebrospinal fluid leptin levels are maintained despite enhanced food intake in progesterone-treated rats. European Journal of Endocrinology144659665. (doi:10.1530/eje.0.1440659)

  • HahnSHaselhorstUQuadbeckBTanSKimmigRMannKJanssenOE2006Decreased soluble leptin receptor levels in women with polycystic ovary syndrome. European Journal of Endocrinology154287294. (doi:10.1530/eje.1.02078)

  • HamnvikOPLiuXPetrouMGongHChamberlandJPKimEHChristophiCAKalesSNChristianiDCMantzorosCS2011Soluble leptin receptor and leptin are associated with baseline adiposity and metabolic risk factors, and predict adiposity, metabolic syndrome, and glucose levels at 2-year follow-up: the Cyprus Metabolism Prospective Cohort Study. Metabolism60987993. (doi:10.1016/j.metabol.2010.09.009)

  • HenryBAGodingJWAlexanderWSTilbrookAJCannyBJDunsheaFRaoAMansellAClarkeIJ1999Central administration of leptin to ovariectomized ewes inhibits food intake without affecting the secretion of hormones from the pituitary gland: evidence for a dissociation of effects on appetite and neuroendocrine function. Endocrinology14011751182.

  • HenryBAGodingJWTilbrookAJDunsheaFRClarkeIJ2001Intracerebroventricular infusion of leptin elevates the secretion of luteinising hormone without affecting food intake in long-term food-restricted sheep, but increases growth hormone irrespective of bodyweight. Journal of Endocrinology1686777. (doi:10.1677/joe.0.1680067)

  • HeymsfieldSBGreenbergASFujiokaKDixonRMKushnerRHuntTLubinaJAPataneJSelfBHuntP1999Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA28215681575. (doi:10.1001/jama.282.16.1568)

  • HillJWEliasCFFukudaMWilliamsKWBerglundEDHollandWLChoYRChuangJCXuYChoiM2010Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metabolism11286297. (doi:10.1016/j.cmet.2010.03.002)

  • IsidoriAMCaprioMStrolloFMorettiCFrajeseGIsidoriAFabbriA1999Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. Journal of Clinical Endocrinology and Metabolism8436733680. (doi:10.1210/jcem.84.10.6082)

  • JainMRPuSKalraPSKalraSP1999Evidence that stimulation of two modalities of pituitary luteinizing hormone release in ovarian steroid-primed ovariectomized rats may involve neuropeptide Y Y1 and Y4 receptors. Endocrinology14051715177. (doi:10.1210/endo.140.11.7107)

  • JanssonNGreenwoodSLJohanssonBRPowellTLJanssonT2003Leptin stimulates the activity of the system A amino acid transporter in human placental villous fragments. Journal of Clinical Endocrinology and Metabolism8812051211. (doi:10.1210/jc.2002-021332)

  • JohnstoneLEHiguchiT2001Food intake and leptin during pregnancy and lactation. Progress in Brain Research133215227. (doi:10.1016/S0079-6123(01)33016-9)

  • JungheimESTraviesoJLCarsonKRMoleyKH2012Obesity and reproductive function. Obstetrics and Gynecology Clinics of North America39479493. (doi:10.1016/j.ogc.2012.09.002)

  • KalraSPKalraPSSahuACrowleyWR1987Gonadal steroids and neurosecretion: facilitatory influence on LHRH and neuropeptide Y. Journal of Steroid Biochemistry27677682. (doi:10.1016/0022-4731(87)90136-1)

  • KaramoutiMKolliaPKallitsarisAVamvakopoulosNKolliosGMessinisIE2009Modulating effect of leptin on basal and follicle stimulating hormone stimulated steroidogenesis in cultured human lutein granulosa cells. Journal of Endocrinological Investigation32415419. (doi:10.1007/BF03346478)

  • KhanSMHamnvikOPBrinkoetterMMantzorosCS2012Leptin as a modulator of neuroendocrine function in humans. Yonsei Medical Journal53671679. (doi:10.3349/ymj.2012.53.4.671)

  • KiessWAnilMBlumWFEnglaroPJuulAAttanasioADotschJRascherW1998Serum leptin levels in children and adolescents with insulin-dependent diabetes mellitus in relation to metabolic control and body mass index. European Journal of Endocrinology138501509. (doi:10.1530/eje.0.1380501)

  • KostrzewaEvan ElburgAASandersNSternheimLAdanRAKasMJ2013Longitudinal changes in the physical activity of adolescents with anorexia nervosa and their influence on body composition and leptin serum levels after recovery. PLoS ONE8e78251. (doi:10.1371/journal.pone.0078251)

  • KowalskaIKinalskiMStraczkowskiMWolczyskiSKinalskaI2001Insulin, leptin, IGF-I and insulin-dependent protein concentrations after insulin-sensitizing therapy in obese women with polycystic ovary syndrome. European Journal of Endocrinology144509515. (doi:10.1530/eje.0.1440509)

  • LaughlinGAYenSS1996Nutritional and endocrine–metabolic aberrations in amenorrheic athletes. Journal of Clinical Endocrinology and Metabolism8143014309. (doi:10.1210/jcem.81.12.8954031)

  • LaughlinGAYenSS1997Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea. Journal of Clinical Endocrinology and Metabolism82318321. (doi:10.1210/jcem.82.1.3840)

  • LaughlinGAMoralesAJYenSS1997Serum leptin levels in women with polycystic ovary syndrome: the role of insulin resistance/hyperinsulinemia. Journal of Clinical Endocrinology and Metabolism8216921696. (doi:10.1210/jcem.82.6.4028)

  • LaughlinGADominguezCEYenSS1998Nutritional and endocrine–metabolic aberrations in women with functional hypothalamic amenorrhea. Journal of Clinical Endocrinology and Metabolism832532. (doi:10.1210/jcem.83.1.4502)

  • LeeJHChanJLSourlasERaptopoulosVMantzorosCS2006Recombinant methionyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy. Journal of Clinical Endocrinology and Metabolism9126052611. (doi:10.1210/jc.2005-1545)

  • LiMGDingGLChenXJLuXPDongLJDongMYYangXFLuXEHuangHF2007Association of serum and follicular fluid leptin concentrations with granulosa cell phosphorylated signal transducer and activator of transcription 3 expression in fertile patients with polycystic ovarian syndrome. Journal of Clinical Endocrinology and Metabolism9247714776. (doi:10.1210/jc.2007-0978)

  • LicinioJCaglayanSOzataMYildizBOde MirandaPBO'KirwanFWhitbyRLiangLCohenPBhasinS2004Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. PNAS10145314536. (doi:10.1073/pnas.0308767101)

  • MagkosFBrennanASweeneyLKangESDoweikoJKarchmerAWMantzorosCS2011Leptin replacement improves postprandial glycemia and insulin sensitivity in human immunodeficiency virus-infected lipoatrophic men treated with pioglitazone: a pilot study. Metabolism6010451049. (doi:10.1016/j.metabol.2010.10.002)

  • MantzorosCSFlierJSRogolAD1997aA longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty. Journal of Clinical Endocrinology and Metabolism8210661070. (doi:10.1210/jcem.82.4.3878)

  • MantzorosCSDunaifAFlierJS1997bLeptin concentrations in the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism8216871691. (doi:10.1210/jcem.82.6.4017)

  • MantzorosCSCramerDWLibermanRFBarbieriRL2000Predictive value of serum and follicular fluid leptin concentrations during assisted reproductive cycles in normal women and in women with the polycystic ovarian syndrome. Human Reproduction15539544. (doi:10.1093/humrep/15.3.539)

  • MantzorosCSMagkosFBrinkoetterMSienkiewiczEDardenoTAKimSYHamnvikOPKoniarisA2011Leptin in human physiology and pathophysiology. American Journal of Physiology. Endocrinology and Metabolism301E567E584. (doi:10.1152/ajpendo.00315.2011)

  • MatareseGLa RoccaCMoonHSHuhJYBrinkoetterMTChouSPernaFGrecoDKilimHPGaoC2013Selective capacity of metreleptin administration to reconstitute CD4+ T-cell number in females with acquired hypoleptinemia. PNAS110E818E827. (doi:10.1073/pnas.1214554110)

  • MatkovicVIlichJZSkugorMBadenhopNEGoelPClairmontAKlisovicDNahhasRWLandollJD1997Leptin is inversely related to age at menarche in human females. Journal of Clinical Endocrinology and Metabolism8232393245. (doi:10.1210/jcem.82.10.4280)

  • MaymoJLPerez PerezASanchez-MargaletVDuenasJLCalvoJCVaroneCL2009Up-regulation of placental leptin by human chorionic gonadotropin. Endocrinology150304313. (doi:10.1210/en.2008-0522)

  • McDonaldJKLumpkinMDDePaoloLV1989Neuropeptide-Y suppresses pulsatile secretion of luteinizing hormone in ovariectomized rats: possible site of action. Endocrinology125186191. (doi:10.1210/endo-125-1-186)

  • MillerKKParulekarMSSchoenfeldEAndersonEHubbardJKlibanskiAGrinspoonSK1998Decreased leptin levels in normal weight women with hypothalamic amenorrhea: the effects of body composition and nutritional intake. Journal of Clinical Endocrinology and Metabolism8323092312. (doi:10.1210/jcem.83.7.4975)

  • MisraMMillerKKAlmazanCRamaswamyKAggarwalAHerzogDBNeubauerGBreuJKlibanskiA2004Hormonal and body composition predictors of soluble leptin receptor, leptin, and free leptin index in adolescent girls with anorexia nervosa and controls and relation to insulin sensitivity. Journal of Clinical Endocrinology and Metabolism8934863495. (doi:10.1210/jc.2003-032251)

  • MistryAMRomsosDR2002Intracerebroventricular leptin administration reduces food intake in pregnant and lactating mice. Experimental Biology and Medicine227616619.

  • MittendorferBHorowitzJFDePaoliAMMcCamishMAPattersonBWKleinS2011Recombinant human leptin treatment does not improve insulin action in obese subjects with type 2 diabetes. Diabetes6014741477. (doi:10.2337/db10-1302)

  • MoonHSMatareseGBrennanAMChamberlandJPLiuXFiorenzaCGMylvaganamGHAbanniLCarboneFWilliamsCJ2011Efficacy of metreleptin in obese patients with type 2 diabetes: cellular and molecular pathways underlying leptin tolerance. Diabetes6016471656. (doi:10.2337/db10-1791)

  • MoonHSChamberlandJPMantzorosCS2012Amylin and leptin activate overlapping signalling pathways in an additive manner in mouse GT1-7 hypothalamic, C(2)C(1)(2) muscle and AML12 liver cell lines. Diabetologia55215225. (doi:10.1007/s00125-011-2332-0)

  • MoonHSDalamagaMKimSYPolyzosSAHamnvikOPMagkosFParuthiJMantzorosCS2013Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals. Endocrine Reviews34377412. (doi:10.1210/er.2012-1053)

  • MorrisonCDDanielJAHolmbergBJDjianeJRaverNGertlerAKeislerDH2001Central infusion of leptin into well-fed and undernourished ewe lambs: effects on feed intake and serum concentrations of growth hormone and luteinizing hormone. Journal of Endocrinology168317324. (doi:10.1677/joe.0.1680317)

  • MorrisonCDWhiteCLWangZLeeSYLawrenceDSCefaluWTZhangZYGettysTW2007Increased hypothalamic protein tyrosine phosphatase 1B contributes to leptin resistance with age. Endocrinology148433440. (doi:10.1210/en.2006-0672)

  • MussoCCochranEJavorEYoungJDepaoliAMGordenP2005The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism54255263. (doi:10.1016/j.metabol.2004.08.021)

  • NaefLWoodsideB2007Prolactin/leptin interactions in the control of food intake in rats. Endocrinology14859775983. (doi:10.1210/en.2007-0442)

  • NagyGSTsiodrasSMartinLDAvihingsanonAGavrilaAHsuWCKarchmerAWMantzorosCS2003Human immunodeficiency virus type 1-related lipoatrophy and lipohypertrophy are associated with serum concentrations of leptin. Clinical Infectious Diseases36795802. (doi:10.1086/367859)

  • NavarroVMRuiz-PinoFSanchez-GarridoMAGarcia-GalianoDHobbsSJManfredi-LozanoMLeonSSangiao-AlvarellosSCastellanoJMCliftonDK2012Role of neurokinin B in the control of female puberty and its modulation by metabolic status. Journal of Neuroscience3223882397. (doi:10.1523/JNEUROSCI.4288-11.2012)

  • OzataMOzdemirICLicinioJ1999Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. Journal of Clinical Endocrinology and Metabolism8436863695. (doi:10.1210/jcem.84.10.5999)

  • OzcanLErginASLuAChungJSarkarSNieDMyersMGJrOzcanU2009Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metabolism93551. (doi:10.1016/j.cmet.2008.12.004)

  • PardiniVCVictoriaIMRochaSMAndradeDGRochaAMPieroniFBMilagresGPurischSVelhoG1998Leptin levels, β-cell function, and insulin sensitivity in families with congenital and acquired generalized lipoatropic diabetes. Journal of Clinical Endocrinology and Metabolism83503508. (doi:10.1210/jcem.83.2.4567)

  • PehlivanovBMitkovM2009Serum leptin levels correlate with clinical and biochemical indices of insulin resistance in women with polycystic ovary syndrome. European Journal of Contraception and Reproductive Health Care14153159. (doi:10.1080/13625180802549962)

  • PinillaLAguilarEDieguezCMillarRPTena-SempereM2012Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiological Reviews9212351316. (doi:10.1152/physrev.00037.2010)

  • PintoSRoseberryAGLiuHDianoSShanabroughMCaiXFriedmanJMHorvathTL2004Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science304110115. (doi:10.1126/science.1089459)

  • PirwanyIRFlemingRSattarNGreerIAWallaceAM2001Circulating leptin concentrations and ovarian function in polycystic ovary syndrome. European Journal of Endocrinology145289294. (doi:10.1530/eje.0.1450289)

  • QuennellJHMulliganACTupsALiuXPhippsSJKempCJHerbisonAEGrattanDRAndersonGM2009Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology15028052812. (doi:10.1210/en.2008-1693)

  • Ramlau-HansenCHThulstrupAMNohrEABondeJPSorensenTIOlsenJ2007Subfecundity in overweight and obese couples. Human Reproduction2216341637. (doi:10.1093/humrep/dem035)

  • ReindollarRHNovakMThoSPMcDonoughPG1986Adult-onset amenorrhea: a study of 262 patients. American Journal of Obstetrics and Gynecology155531543. (doi:10.1016/0002-9378(86)90274-7)

  • ReznikovAGMcCannSM1993Effects of neuropeptide Y on gonadotropin and prolactin release in normal, castrated or flutamide-treated male rats. Neuroendocrinology5711481154. (doi:10.1159/000126481)

  • RoaJGarcia-GalianoDVarelaLSanchez-GarridoMAPinedaRCastellanoJMRuiz-PinoFRomeroMAguilarELopezM2009The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system. Endocrinology15050165026. (doi:10.1210/en.2009-0096)

  • RomualdiDCampagnaGSelvaggiLJrCentoRProtoCLanzoneAGuidoM2008Metformin treatment does not affect total leptin levels and free leptin index in obese patients with polycystic ovary syndrome. Fertility and Sterility8912731276. (doi:10.1016/j.fertnstert.2007.05.004)

  • RosenbaumMLeibelRL1999Clinical review 107: role of gonadal steroids in the sexual dimorphisms in body composition and circulating concentrations of leptin. Journal of Clinical Endocrinology and Metabolism8417841789. (doi:10.1210/jcem.84.6.5787)

  • SabatinoFDCollinsPMcDonaldJK1989Neuropeptide-Y stimulation of luteinizing hormone-releasing hormone secretion from the median eminence in vitro by estrogen-dependent and extracellular Ca2+-independent mechanisms. Endocrinology12420892098. (doi:10.1210/endo-124-5-2089)

  • SadagurskiMLeshanRLPattersonCRozzoAKuznetsovaASkorupskiJJonesJCDepinhoRAMyersMGJrWhiteMF2012IRS2, signaling in LepR-b neurons suppresses FoxO1 to control energy balance independently of leptin action. Cell Metabolism15703712. (doi:10.1016/j.cmet.2012.04.011)

  • Sanchez-GarridoMATena-SempereM2013Metabolic control of puberty: roles of leptin and kisspeptins. Hormones and Behavior64187194. (doi:10.1016/j.yhbeh.2013.01.014)

  • SchiothHBKakizakiYKohsakaASudaTWatanobeH2001Agouti-related peptide prevents steroid-induced luteinizing hormone and prolactin surges in female rats. Neuroreport12687690. (doi:10.1097/00001756-200103260-00014)

  • von SchnurbeinJMossANagelSAMuehlederHDebatinKMFarooqiISWabitschM2012Leptin substitution results in the induction of menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism. Hormone Research in Paediatrics77127133. (doi:10.1159/000336003)

  • SchubringCEnglaroPSieblerTBlumWFDemirakcaTKratzschJKiessW1998Longitudinal analysis of maternal serum leptin levels during pregnancy, at birth and up to six weeks after birth: relation to body mass index, skinfolds, sex steroids and umbilical cord blood leptin levels. Hormone Research50276283. (doi:10.1159/000023290)

  • SeeberRMSmithJTWaddellBJ2002Plasma leptin-binding activity and hypothalamic leptin receptor expression during pregnancy and lactation in the rat. Biological Reproduction6617621767. (doi:10.1095/biolreprod66.6.1762)

  • SienkiewiczEMagkosFAronisKNBrinkoetterMChamberlandJPChouSArampatziKMGaoCKoniarisAMantzorosCS2011Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism6012111221. (doi:10.1016/j.metabol.2011.05.016)

  • Sir-PetermannTPiwonkaVPerezFMaliqueoMRecabarrenSEWildtL1999Are circulating leptin and luteinizing hormone synchronized in patients with polycystic ovary syndrome?Human Reproduction1414351439. (doi:10.1093/humrep/14.6.1435)

  • SoyupekSArmaganASerelTAHoscanMBPerkHKaraozECandirO2005Leptin expression in the testicular tissue of fertile and infertile men. Archives of Andrology51239246. (doi:10.1080/01485010590919666)

  • TeerdsKJde RooijDGKeijerJ2011Functional relationship between obesity and male reproduction: from humans to animal models. Human Reproduction Update17667683. (doi:10.1093/humupd/dmr017)

  • Tena-SempereM2007Roles of ghrelin and leptin in the control of reproductive function. Neuroendocrinology86229241. (doi:10.1159/000108410)

  • Tena-SempereMPinillaLGonzalezLCDieguezCCasanuevaFFAguilarE1999Leptin inhibits testosterone secretion from adult rat testis in vitro. Journal of Endocrinology161211218. (doi:10.1677/joe.0.1610211)

  • Tena-SempereMPinillaLGonzalezLCNavarroJDieguezCCasanuevaFFAguilarE2000In vitro pituitary and testicular effects of the leptin-related synthetic peptide leptin(116–130) amide involve actions both similar to and distinct from those of the native leptin molecule in the adult rat. European Journal of Endocrinology142406410. (doi:10.1530/eje.0.1420406)

  • TessierDRFerraroZMGruslinA2013Role of leptin in pregnancy: consequences of maternal obesity. Placenta34205211. (doi:10.1016/j.placenta.2012.11.035)

  • TfayliHUlnachJWLeeSSutton-TyrrellKArslanianS2011Drospirenone/ethinyl estradiol versus rosiglitazone treatment in overweight adolescents with polycystic ovary syndrome: comparison of metabolic, hormonal, and cardiovascular risk factors. Journal of Clinical Endocrinology and Metabolism9613111319. (doi:10.1210/jc.2010-2547)

  • ThongFSMcLeanCGrahamTE2000Plasma leptin in female athletes: relationship with body fat, reproductive, nutritional, and endocrine factors. Journal of Applied Physiology8820372044.

  • TortorielloDVMcMinnJChuaSC2004Dietary-induced obesity and hypothalamic infertility in female DBA/2J mice. Endocrinology14512381247. (doi:10.1210/en.2003-1406)

  • UrbanJHDasILevineJE1996Steroid modulation of neuropeptide Y-induced luteinizing hormone releasing hormone release from median eminence fragments from male rats. Neuroendocrinology63112119. (doi:10.1159/000126947)

  • VulliemozNRXiaoEXia-ZhangLWardlawSLFerinM2005Central infusion of agouti-related peptide suppresses pulsatile luteinizing hormone release in the ovariectomized rhesus monkey. Endocrinology146784789. (doi:10.1210/en.2004-1093)

  • WaltersKAAllanCMHandelsmanDJ2012Rodent models for human polycystic ovary syndrome. Biological Reproduction149112. (doi:10.1095/biolreprod.111.097808)

  • WangMYChenLClarkGOLeeYStevensRDIlkayevaORWennerBRBainJRCharronMJNewgardCB2010Leptin therapy in insulin-deficient type I diabetes. PNAS10748134819. (doi:10.1073/pnas.0909422107)

  • WarrenMPVoussoughianFGeerEBHyleEPAdbergCLRamosRH1999Functional hypothalamic amenorrhea: hypoleptinemia and disordered eating. Journal of Clinical Endocrinology and Metabolism84873877. (doi:10.1210/jcem.84.3.5551)

  • WatanobeHSchiothHBWikbergJESudaT1999The melanocortin 4 receptor mediates leptin stimulation of luteinizing hormone and prolactin surges in steroid-primed ovariectomized rats. Biochemical and Biophysical Research Communications257860864. (doi:10.1006/bbrc.1999.0547)

  • WeltCKChanJLBullenJMurphyRSmithPDePaoliAMKaralisAMantzorosCS2004Recombinant human leptin in women with hypothalamic amenorrhea. New England Journal of Medicine351987997. (doi:10.1056/NEJMoa040388)

  • WhiteVGonzalezECapobiancoEPustovrhCMartinezNHigaRBaierMJawerbaumA2006Leptin modulates nitric oxide production and lipid metabolism in human placenta. Reproduction Fertility and Development18425432. (doi:10.1071/RD05105)

  • YannakouliaMYiannakourisNBluherSMatalasALKlimis-ZacasDMantzorosCS2003Body fat mass and macronutrient intake in relation to circulating soluble leptin receptor, free leptin index, adiponectin, and resistin concentrations in healthy humans. Journal of Clinical Endocrinology and Metabolism8817301736. (doi:10.1210/jc.2002-021604)

  • YildizhanRIlhanGAYildizhanBKolusariAAdaliEBugdayciG2011Serum retinol-binding protein 4, leptin, and plasma asymmetric dimethylarginine levels in obese and nonobese young women with polycystic ovary syndrome. Fertility and Sterility96246250. (doi:10.1016/j.fertnstert.2011.04.073)

  • YuWHKimuraMWalczewskaAKaranthSMcCannSM1997aRole of leptin in hypothalamic–pituitary function. PNAS9410231028. (doi:10.1073/pnas.94.3.1023)

  • YuWHWalczewskaAKaranthSMcCannSM1997bNitric oxide mediates leptin-induced luteinizing hormone-releasing hormone (LHRH) and LHRH and leptin-induced LH release from the pituitary gland. Endocrinology13850555058. (doi:10.1210/endo.138.11.5649)

This paper is part of a thematic review section on 20 Years of Leptin. The Guest Editor for this section was Sir Stephen O'Rahilly, University of Cambridge, Cambridge, UK.

If the inline PDF is not rendering correctly, you can download the PDF file here.

 

      Society for Endocrinology

Related Articles

Article Information

Metrics

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 1724 1724 229
PDF Downloads 250 250 38

Altmetrics

Figures

  • View in gallery

    Schematic illustration of the interactions of leptin with the hypothalamic–pituitary–gonadal axis. Leptin stimulates POMC/CART and Glut neurons and inhibits AgRP/NPY and GABA neurons to modulate reproduction centrally. At the ovaries, leptin can have different effects depending on the metabolic status. AgRP, agouti-related peptide; CART, cocaine and amphetamine-regulated transcript; FSH, follicle-stimulating hormone; GABA, gamma-aminobutyric acid; Glut, glutamate; GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; NKB, neurokinin B; NPY, neuropeptide Y; PMV, ventral premammillary nucleus; POMC, proopiomelanocortin.

References

AcromiteMZiotopoulouMOrlovaCMantzorosC2004Increased leptin levels in preeclampsia: associations with BMI, estrogen and SHBG levels. Hormones34652. (doi:10.14310/horm.2002.11111)

AgarwalSKVogelKWeitsmanSRMagoffinDA1999Leptin antagonizes the insulin-like growth factor-I augmentation of steroidogenesis in granulosa and theca cells of the human ovary. Journal of Clinical Endocrinology and Metabolism8410721076. (doi:10.1210/jcem.84.3.5543)

AmstaldenMGarciaMRStankoRLNizielskiSEMorrisonCDKeislerDHWilliamsGL2002Central infusion of recombinant ovine leptin normalizes plasma insulin and stimulates a novel hypersecretion of luteinizing hormone after short-term fasting in mature beef cows. Biological Reproduction6615551561. (doi:10.1095/biolreprod66.5.1555)

AndreelliFHanaire-BroutinHLavilleMTauberJPRiouJPThivoletC2000Normal reproductive function in leptin-deficient patients with lipoatropic diabetes. Journal of Clinical Endocrinology and Metabolism85715719. (doi:10.1210/jcem.85.2.6392)

AndricoSGamberaASpecchiaCPellegriniCFalsettiLSartoriE2002Leptin in functional hypothalamic amenorrhoea. Human Reproduction1720432048. (doi:10.1093/humrep/17.8.2043)

AquilaSGentileMMiddeaECatalanoSMorelliCPezziVAndoS2005Leptin secretion by human ejaculated spermatozoa. Journal of Clinical Endocrinology and Metabolism9047534761. (doi:10.1210/jc.2004-2233)

BackholerKSmithJTRaoAPereiraAIqbalJOgawaSLiQClarkeIJ2010Kisspeptin cells in the ewe brain respond to leptin and communicate with neuropeptide Y and proopiomelanocortin cells. Endocrinology15122332243. (doi:10.1210/en.2009-1190)

BanksWAMcLayRNKastinAJSarmientoUScullyS1999Passage of leptin across the blood-testis barrier. American Journal of Physiology276E1099E1104.

BatesSHStearnsWHDundonTASchubertMTsoAWWangYBanksASLaveryHJHaqAKMaratos-FlierE2003STAT3 signalling is required for leptin regulation of energy balance but not reproduction. Nature421856859. (doi:10.1038/nature01388)

BelliSHGraffignaMNOnetoAOteroPSchurmanLLevalleOA2004Effect of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome. Fertility and Sterility81624629. (doi:10.1016/j.fertnstert.2003.08.024)

BergaSLMortolaJFGirtonLSuhBLaughlinGPhamPYenSS1989Neuroendocrine aberrations in women with functional hypothalamic amenorrhea. Journal of Clinical Endocrinology and Metabolism68301308. (doi:10.1210/jcem-68-2-301)

BjorbaekCElmquistJKFrantzJDShoelsonSEFlierJS1998Identification of SOCS-3 as a potential mediator of central leptin resistance. Molecular Cell1619625. (doi:10.1016/S1097-2765(00)80062-3)

BjornholmMMunzbergHLeshanRLVillanuevaECBatesSHLouisGWJonesJCIshida-TakahashiRBjorbaekCMyersMGJr2007Mice lacking inhibitory leptin receptor signals are lean with normal endocrine function. Journal of Clinical Investigation11713541360. (doi:10.1172/JCI30688)

BluherSMantzorosCS2007Leptin in reproduction. Current Opinion in Endocrinology Diabetes and Obesity14458464. (doi:10.1097/MED.0b013e3282f1cfdc)

BohlenFKratzschJMuellerMSeidelBFriedman-EinatMWitzigmannHTeupserDKoernerAStorckMThieryJ2007Leptin inhibits cell growth of human vascular smooth muscle cells. Vascular Pharmacology466771. (doi:10.1016/j.vph.2006.06.014)

BombaMGamberaABoniniLPeroniMNeriFScagliolaPNacinovichR2007Endocrine profiles and neuropsychologic correlates of functional hypothalamic amenorrhea in adolescents. Fertility and Sterility87876885. (doi:10.1016/j.fertnstert.2006.09.011)

BrandJSvan der TweelIGrobbeeDEEmmelot-VonkMHvan der SchouwYT2011Testosterone, sex hormone-binding globulin and the metabolic syndrome: a systematic review and meta-analysis of observational studies. International Journal of Epidemiology40189207. (doi:10.1093/ije/dyq158)

BrennanAMLeeJHTsiodrasSChanJLDoweikoJChimientiSNWadhwaSGKarchmerAWMantzorosCS2009r-metHuLeptin improves highly active antiretroviral therapy-induced lipoatrophy and the metabolic syndrome, but not through altering circulating IGF and IGF-binding protein levels: observational and interventional studies in humans. European Journal of Endocrinology160173176. (doi:10.1530/EJE-08-0597)

BrinkoetterMMagkosFVamviniMMantzorosCS2011Leptin treatment reduces body fat but does not affect lean body mass or the myostatin–follistatin–activin axis in lean hypoleptinemic women. American Journal of Physiology. Endocrinology and Metabolism301E99E104. (doi:10.1152/ajpendo.00146.2011)

BruntonPJRussellJA2008The expectant brain: adapting for motherhood. Nature Reviews. Neuroscience91125. (doi:10.1038/nrn2280)

BrzechffaPRJakimiukAJAgarwalSKWeitsmanSRBuyalosRPMagoffinDA1996Serum immunoreactive leptin concentrations in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism8141664169. (doi:10.1210/jcem.81.11.8923878)

CaprioMIsidoriAMCartaARMorettiCDufauMLFabbriA1999Expression of functional leptin receptors in rodent Leydig cells. Endocrinology14049394947. (doi:10.1210/endo.140.11.7088)

CarminaEBucchieriSMansuetoPRiniGFerinMLoboRA2009Circulating levels of adipose products and differences in fat distribution in the ovulatory and anovulatory phenotypes of polycystic ovary syndrome. Fertility and Sterility9113321335. (doi:10.1016/j.fertnstert.2008.03.007)

CastellanoJMNavarroVMFernandez-FernandezRRoaJVigoEPinedaRDieguezCAguilarEPinillaLTena-SempereM2006Expression of hypothalamic KiSS-1 system and rescue of defective gonadotropic responses by kisspeptin in streptozotocin-induced diabetic male rats. Diabetes5526022610. (doi:10.2337/db05-1584)

ChallierJGaltierMBinteinTCortezALepercqJHauguel-de MouzonS2003Placental leptin receptor isoforms in normal and pathological pregnancies. Placenta249299. (doi:10.1053/plac.2002.0805)

ChanJLMantzorosCS2005Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. Lancet3667485. (doi:10.1016/S0140-6736(05)66830-4)

ChanJLHeistKDePaoliAMVeldhuisJDMantzorosCS2003The role of falling leptin levels in the neuroendocrine and metabolic adaptation to short-term starvation in healthy men. Journal of Clinical Investigation11114091421. (doi:10.1172/JCI200317490)

ChanJLBullenJStoynevaVDepaoliAMAddyCMantzorosCS2005Recombinant methionyl human leptin administration to achieve high physiologic or pharmacologic leptin levels does not alter circulating inflammatory marker levels in humans with leptin sufficiency or excess. Journal of Clinical Endocrinology and Metabolism9016181624. (doi:10.1210/jc.2004-1921)

ChanJLWilliamsCJRacitiPBlakemanJKelesidisTKelesidisIJohnsonMLThornerMOMantzorosCS2008Leptin does not mediate short-term fasting-induced changes in growth hormone pulsatility but increases IGF-I in leptin deficiency states. Journal of Clinical Endocrinology and Metabolism9328192827. (doi:10.1210/jc.2008-0056)

ChardonnensDCameoPAubertMLPralongFPIslamiDCampanaAGaillardRCBischofP1999Modulation of human cytotrophoblastic leptin secretion by interleukin-1α and 17β-oestradiol and its effect on HCG secretion. Molecular Human Reproduction510771082. (doi:10.1093/molehr/5.11.1077)

ChenXJiaXQiaoJGuanYKangJ2013Adipokines in reproductive function: a link between obesity and polycystic ovary syndrome. Journal of Molecular Endocrinology50R21R37. (doi:10.1530/JME-12-0247)

ChouSHChamberlandJPLiuXMatareseGGaoCStefanakisRBrinkoetterMTGongHArampatziKMantzorosCS2011Leptin is an effective treatment for hypothalamic amenorrhea. PNAS10865856590. (doi:10.1073/pnas.1015674108)

CioffiJAShaferAWZupancicTJSmith-GburJMikhailAPlatikaDSnodgrassHR1996Novel B219/OB receptor isoforms: possible role of leptin in hematopoiesis and reproduction. Nature Medicine2585589. (doi:10.1038/nm0596-585)

CobbKLBachrachLKSowersMNievesJGreendaleGAKentKKBrownBWJrPettitKHarperDMKelseyJL2007The effect of oral contraceptives on bone mass and stress fractures in female runners. Medicine and Science in Sports and Exercise3914641473. (doi:10.1249/mss.0b013e318074e532)

CodnerEMerinoPMTena-SempereM2012Female reproduction and type 1 diabetes: from mechanisms to clinical findings. Human Reproduction Update18568585. (doi:10.1093/humupd/dms024)

ConsidineRVSinhaMKHeimanMLKriauciunasAStephensTWNyceMROhannesianJPMarcoCCMcKeeLJBauerTL1996Serum immunoreactive-leptin concentrations in normal-weight and obese humans. New England Journal of Medicine334292295. (doi:10.1056/NEJM199602013340503)

CorrMDe SouzaMJToombsRJWilliamsNI2011Circulating leptin concentrations do not distinguish menstrual status in exercising women. Human Reproduction26685694. (doi:10.1093/humrep/deq375)

CowleyMASmartJLRubinsteinMCerdanMGDianoSHorvathTLConeRDLowMJ2001Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature411480484. (doi:10.1038/35078085)

CravoRMFrazaoRPerelloMOsborne-LawrenceSWilliamsKWZigmanJMViannaCEliasCF2013Leptin signaling in Kiss1 neurons arises after pubertal development. PLoS ONE8e58698. (doi:10.1371/journal.pone.0058698)

DandonaPDhindsaS2011Update: hypogonadotropic hypogonadism in type 2 diabetes and obesity. Journal of Clinical Endocrinology and Metabolism9626432651. (doi:10.1210/jc.2010-2724)

DardenoTAChouSHMoonHSChamberlandJPFiorenzaCGMantzorosCS2010Leptin in human physiology and therapeutics. Frontiers in Neuroendocrinology31377393. (doi:10.1016/j.yfrne.2010.06.002)

DeiMSeravalliVBruniVBalziDPasquaA2008Predictors of recovery of ovarian function after weight gain in subjects with amenorrhea related to restrictive eating disorders. Gynecological Endocrinology24459464. (doi:10.1080/09513590802246141)

DonatoJJrCravoRMFrazaoRGautronLScottMMLacheyJCastroIAMargathoLOLeeSLeeC2011Leptin's effect on puberty in mice is relayed by the ventral premammillary nucleus and does not require signaling in Kiss1 neurons. Journal of Clinical Investigation121355368. (doi:10.1172/JCI45106)

DucherGTurnerAIKukuljanSPantanoKJCarlsonJLWilliamsNIDe SouzaMJ2011Obstacles in the optimization of bone health outcomes in the female athlete triad. Sports Medicine41587607. (doi:10.2165/11588770-000000000-00000)

DunnSLBjornholmMBatesSHChenZSeifertMMyersMGJr2005Feedback inhibition of leptin receptor/Jak2 signaling via Tyr1138 of the leptin receptor and suppressor of cytokine signaling 3. Molecular Endocrinology19925938. (doi:10.1210/me.2004-0353)

EbiharaKKusakabeTHirataMMasuzakiHMiyanagaFKobayashiNTanakaTChushoHMiyazawaTHayashiT2007Efficacy and safety of leptin-replacement therapy and possible mechanisms of leptin actions in patients with generalized lipodystrophy. Journal of Clinical Endocrinology and Metabolism92532541. (doi:10.1210/jc.2006-1546)

El-HaschimiKPierrozDDHilemanSMBjorbaekCFlierJS2000Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obesity. Journal of Clinical Investigation10518271832. (doi:10.1172/JCI9842)

EliasCF2012Leptin action in pubertal development: recent advances and unanswered questions. Trends in Endocrinology and Metabolism23915. (doi:10.1016/j.tem.2011.09.002)

EliasCFPurohitD2013Leptin signaling and circuits in puberty and fertility. Cellular and Molecular Life Sciences70841862. (doi:10.1007/s00018-012-1095-1)

FarleyDMChoiJDudleyDJLiCJenkinsSLMyattLNathanielszPW2010Placental amino acid transport and placental leptin resistance in pregnancies complicated by maternal obesity. Placenta31718724. (doi:10.1016/j.placenta.2010.06.006)

FarooqiISMatareseGLordGMKeoghJMLawrenceEAgwuCSannaVJebbSAPernaFFontanaS2002Beneficial effects of leptin on obesity, T cell hyporesponsiveness, and neuroendocrine/metabolic dysfunction of human congenital leptin deficiency. Journal of Clinical Investigation11010931103. (doi:10.1172/JCI0215693)

FiorenzaCGChouSHMantzorosCS2011Lipodystrophy: pathophysiology and advances in treatment. Nature Reviews. Endocrinology7137150. (doi:10.1038/nrendo.2010.199)

FrischREMcArthurJW1974Menstrual cycles: fatness as a determinant of minimum weight for height necessary for their maintenance or onset. Science185949951. (doi:10.1126/science.185.4155.949)

Garcia-MayorRVAndradeMARiosMLageMDieguezCCasanuevaFF1997Serum leptin levels in normal children: relationship to age, gender, body mass index, pituitary–gonadal hormones, and pubertal stage. Journal of Clinical Endocrinology and Metabolism8228492855. (doi:10.1210/jcem.82.9.4235)

GaronnaEBothamKMBirdseyGMRandiAMGonzalez-PerezRRWheeler-JonesCP2011Vascular endothelial growth factor receptor-2 couples cyclo-oxygenase-2 with pro-angiogenic actions of leptin on human endothelial cells. PLoS ONE6e18823. (doi:10.1371/journal.pone.0018823)

GenazzaniADPetragliaFGastaldiMGambaOCorazzaFD'AmbrogioGGenazzaniAR1996Growth hormone (GH)-releasing hormone-induced GH response in hypothalamic amenorrhea: evidence of altered central neuromodulation. Fertility and Sterility65935938.

GenazzaniADBersiCLuisiSFruzzettiFMalavasiBLuisiMPetragliaFGenazzaniAR2001Increased adrenal steroid secretion in response to CRF in women with hypothalamic amenorrhea. Journal of Steroid Biochemistry and Molecular Biology78247252. (doi:10.1016/S0960-0760(01)00094-2)

GenazzaniADRicchieriFLanzoniCStrucchiCJasonniVM2006Diagnostic and therapeutic approach to hypothalamic amenorrhea. Annals of the New York Academy of Sciences1092103113. (doi:10.1196/annals.1365.009)

GordonCM2010Clinical practice. Functional hypothalamic amenorrhea. New England Journal of Medicine363365371. (doi:10.1056/NEJMcp0912024)

GordonCMGraceEEmansSJGoodmanECrawfordMHLeboffMS1999Changes in bone turnover markers and menstrual function after short-term oral DHEA in young women with anorexia nervosa. Journal of Bone and Mineral Research14136145. (doi:10.1359/jbmr.1999.14.1.136)

GrinspoonSThomasLMillerKHerzogDKlibanskiA2002Effects of recombinant human IGF-I and oral contraceptive administration on bone density in anorexia nervosa. Journal of Clinical Endocrinology and Metabolism8728832891. (doi:10.1210/jcem.87.6.8574)

GruesoERochaMPuertaM2001Plasma and cerebrospinal fluid leptin levels are maintained despite enhanced food intake in progesterone-treated rats. European Journal of Endocrinology144659665. (doi:10.1530/eje.0.1440659)

HahnSHaselhorstUQuadbeckBTanSKimmigRMannKJanssenOE2006Decreased soluble leptin receptor levels in women with polycystic ovary syndrome. European Journal of Endocrinology154287294. (doi:10.1530/eje.1.02078)

HamnvikOPLiuXPetrouMGongHChamberlandJPKimEHChristophiCAKalesSNChristianiDCMantzorosCS2011Soluble leptin receptor and leptin are associated with baseline adiposity and metabolic risk factors, and predict adiposity, metabolic syndrome, and glucose levels at 2-year follow-up: the Cyprus Metabolism Prospective Cohort Study. Metabolism60987993. (doi:10.1016/j.metabol.2010.09.009)

HenryBAGodingJWAlexanderWSTilbrookAJCannyBJDunsheaFRaoAMansellAClarkeIJ1999Central administration of leptin to ovariectomized ewes inhibits food intake without affecting the secretion of hormones from the pituitary gland: evidence for a dissociation of effects on appetite and neuroendocrine function. Endocrinology14011751182.

HenryBAGodingJWTilbrookAJDunsheaFRClarkeIJ2001Intracerebroventricular infusion of leptin elevates the secretion of luteinising hormone without affecting food intake in long-term food-restricted sheep, but increases growth hormone irrespective of bodyweight. Journal of Endocrinology1686777. (doi:10.1677/joe.0.1680067)

HeymsfieldSBGreenbergASFujiokaKDixonRMKushnerRHuntTLubinaJAPataneJSelfBHuntP1999Recombinant leptin for weight loss in obese and lean adults: a randomized, controlled, dose-escalation trial. JAMA28215681575. (doi:10.1001/jama.282.16.1568)

HillJWEliasCFFukudaMWilliamsKWBerglundEDHollandWLChoYRChuangJCXuYChoiM2010Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility. Cell Metabolism11286297. (doi:10.1016/j.cmet.2010.03.002)

IsidoriAMCaprioMStrolloFMorettiCFrajeseGIsidoriAFabbriA1999Leptin and androgens in male obesity: evidence for leptin contribution to reduced androgen levels. Journal of Clinical Endocrinology and Metabolism8436733680. (doi:10.1210/jcem.84.10.6082)

JainMRPuSKalraPSKalraSP1999Evidence that stimulation of two modalities of pituitary luteinizing hormone release in ovarian steroid-primed ovariectomized rats may involve neuropeptide Y Y1 and Y4 receptors. Endocrinology14051715177. (doi:10.1210/endo.140.11.7107)

JanssonNGreenwoodSLJohanssonBRPowellTLJanssonT2003Leptin stimulates the activity of the system A amino acid transporter in human placental villous fragments. Journal of Clinical Endocrinology and Metabolism8812051211. (doi:10.1210/jc.2002-021332)

JohnstoneLEHiguchiT2001Food intake and leptin during pregnancy and lactation. Progress in Brain Research133215227. (doi:10.1016/S0079-6123(01)33016-9)

JungheimESTraviesoJLCarsonKRMoleyKH2012Obesity and reproductive function. Obstetrics and Gynecology Clinics of North America39479493. (doi:10.1016/j.ogc.2012.09.002)

KalraSPKalraPSSahuACrowleyWR1987Gonadal steroids and neurosecretion: facilitatory influence on LHRH and neuropeptide Y. Journal of Steroid Biochemistry27677682. (doi:10.1016/0022-4731(87)90136-1)

KaramoutiMKolliaPKallitsarisAVamvakopoulosNKolliosGMessinisIE2009Modulating effect of leptin on basal and follicle stimulating hormone stimulated steroidogenesis in cultured human lutein granulosa cells. Journal of Endocrinological Investigation32415419. (doi:10.1007/BF03346478)

KhanSMHamnvikOPBrinkoetterMMantzorosCS2012Leptin as a modulator of neuroendocrine function in humans. Yonsei Medical Journal53671679. (doi:10.3349/ymj.2012.53.4.671)

KiessWAnilMBlumWFEnglaroPJuulAAttanasioADotschJRascherW1998Serum leptin levels in children and adolescents with insulin-dependent diabetes mellitus in relation to metabolic control and body mass index. European Journal of Endocrinology138501509. (doi:10.1530/eje.0.1380501)

KostrzewaEvan ElburgAASandersNSternheimLAdanRAKasMJ2013Longitudinal changes in the physical activity of adolescents with anorexia nervosa and their influence on body composition and leptin serum levels after recovery. PLoS ONE8e78251. (doi:10.1371/journal.pone.0078251)

KowalskaIKinalskiMStraczkowskiMWolczyskiSKinalskaI2001Insulin, leptin, IGF-I and insulin-dependent protein concentrations after insulin-sensitizing therapy in obese women with polycystic ovary syndrome. European Journal of Endocrinology144509515. (doi:10.1530/eje.0.1440509)

LaughlinGAYenSS1996Nutritional and endocrine–metabolic aberrations in amenorrheic athletes. Journal of Clinical Endocrinology and Metabolism8143014309. (doi:10.1210/jcem.81.12.8954031)

LaughlinGAYenSS1997Hypoleptinemia in women athletes: absence of a diurnal rhythm with amenorrhea. Journal of Clinical Endocrinology and Metabolism82318321. (doi:10.1210/jcem.82.1.3840)

LaughlinGAMoralesAJYenSS1997Serum leptin levels in women with polycystic ovary syndrome: the role of insulin resistance/hyperinsulinemia. Journal of Clinical Endocrinology and Metabolism8216921696. (doi:10.1210/jcem.82.6.4028)

LaughlinGADominguezCEYenSS1998Nutritional and endocrine–metabolic aberrations in women with functional hypothalamic amenorrhea. Journal of Clinical Endocrinology and Metabolism832532. (doi:10.1210/jcem.83.1.4502)

LeeJHChanJLSourlasERaptopoulosVMantzorosCS2006Recombinant methionyl human leptin therapy in replacement doses improves insulin resistance and metabolic profile in patients with lipoatrophy and metabolic syndrome induced by the highly active antiretroviral therapy. Journal of Clinical Endocrinology and Metabolism9126052611. (doi:10.1210/jc.2005-1545)

LiMGDingGLChenXJLuXPDongLJDongMYYangXFLuXEHuangHF2007Association of serum and follicular fluid leptin concentrations with granulosa cell phosphorylated signal transducer and activator of transcription 3 expression in fertile patients with polycystic ovarian syndrome. Journal of Clinical Endocrinology and Metabolism9247714776. (doi:10.1210/jc.2007-0978)

LicinioJCaglayanSOzataMYildizBOde MirandaPBO'KirwanFWhitbyRLiangLCohenPBhasinS2004Phenotypic effects of leptin replacement on morbid obesity, diabetes mellitus, hypogonadism, and behavior in leptin-deficient adults. PNAS10145314536. (doi:10.1073/pnas.0308767101)

MagkosFBrennanASweeneyLKangESDoweikoJKarchmerAWMantzorosCS2011Leptin replacement improves postprandial glycemia and insulin sensitivity in human immunodeficiency virus-infected lipoatrophic men treated with pioglitazone: a pilot study. Metabolism6010451049. (doi:10.1016/j.metabol.2010.10.002)

MantzorosCSFlierJSRogolAD1997aA longitudinal assessment of hormonal and physical alterations during normal puberty in boys. V. Rising leptin levels may signal the onset of puberty. Journal of Clinical Endocrinology and Metabolism8210661070. (doi:10.1210/jcem.82.4.3878)

MantzorosCSDunaifAFlierJS1997bLeptin concentrations in the polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism8216871691. (doi:10.1210/jcem.82.6.4017)

MantzorosCSCramerDWLibermanRFBarbieriRL2000Predictive value of serum and follicular fluid leptin concentrations during assisted reproductive cycles in normal women and in women with the polycystic ovarian syndrome. Human Reproduction15539544. (doi:10.1093/humrep/15.3.539)

MantzorosCSMagkosFBrinkoetterMSienkiewiczEDardenoTAKimSYHamnvikOPKoniarisA2011Leptin in human physiology and pathophysiology. American Journal of Physiology. Endocrinology and Metabolism301E567E584. (doi:10.1152/ajpendo.00315.2011)

MatareseGLa RoccaCMoonHSHuhJYBrinkoetterMTChouSPernaFGrecoDKilimHPGaoC2013Selective capacity of metreleptin administration to reconstitute CD4+ T-cell number in females with acquired hypoleptinemia. PNAS110E818E827. (doi:10.1073/pnas.1214554110)

MatkovicVIlichJZSkugorMBadenhopNEGoelPClairmontAKlisovicDNahhasRWLandollJD1997Leptin is inversely related to age at menarche in human females. Journal of Clinical Endocrinology and Metabolism8232393245. (doi:10.1210/jcem.82.10.4280)

MaymoJLPerez PerezASanchez-MargaletVDuenasJLCalvoJCVaroneCL2009Up-regulation of placental leptin by human chorionic gonadotropin. Endocrinology150304313. (doi:10.1210/en.2008-0522)

McDonaldJKLumpkinMDDePaoloLV1989Neuropeptide-Y suppresses pulsatile secretion of luteinizing hormone in ovariectomized rats: possible site of action. Endocrinology125186191. (doi:10.1210/endo-125-1-186)

MillerKKParulekarMSSchoenfeldEAndersonEHubbardJKlibanskiAGrinspoonSK1998Decreased leptin levels in normal weight women with hypothalamic amenorrhea: the effects of body composition and nutritional intake. Journal of Clinical Endocrinology and Metabolism8323092312. (doi:10.1210/jcem.83.7.4975)

MisraMMillerKKAlmazanCRamaswamyKAggarwalAHerzogDBNeubauerGBreuJKlibanskiA2004Hormonal and body composition predictors of soluble leptin receptor, leptin, and free leptin index in adolescent girls with anorexia nervosa and controls and relation to insulin sensitivity. Journal of Clinical Endocrinology and Metabolism8934863495. (doi:10.1210/jc.2003-032251)

MistryAMRomsosDR2002Intracerebroventricular leptin administration reduces food intake in pregnant and lactating mice. Experimental Biology and Medicine227616619.

MittendorferBHorowitzJFDePaoliAMMcCamishMAPattersonBWKleinS2011Recombinant human leptin treatment does not improve insulin action in obese subjects with type 2 diabetes. Diabetes6014741477. (doi:10.2337/db10-1302)

MoonHSMatareseGBrennanAMChamberlandJPLiuXFiorenzaCGMylvaganamGHAbanniLCarboneFWilliamsCJ2011Efficacy of metreleptin in obese patients with type 2 diabetes: cellular and molecular pathways underlying leptin tolerance. Diabetes6016471656. (doi:10.2337/db10-1791)

MoonHSChamberlandJPMantzorosCS2012Amylin and leptin activate overlapping signalling pathways in an additive manner in mouse GT1-7 hypothalamic, C(2)C(1)(2) muscle and AML12 liver cell lines. Diabetologia55215225. (doi:10.1007/s00125-011-2332-0)

MoonHSDalamagaMKimSYPolyzosSAHamnvikOPMagkosFParuthiJMantzorosCS2013Leptin's role in lipodystrophic and nonlipodystrophic insulin-resistant and diabetic individuals. Endocrine Reviews34377412. (doi:10.1210/er.2012-1053)

MorrisonCDDanielJAHolmbergBJDjianeJRaverNGertlerAKeislerDH2001Central infusion of leptin into well-fed and undernourished ewe lambs: effects on feed intake and serum concentrations of growth hormone and luteinizing hormone. Journal of Endocrinology168317324. (doi:10.1677/joe.0.1680317)

MorrisonCDWhiteCLWangZLeeSYLawrenceDSCefaluWTZhangZYGettysTW2007Increased hypothalamic protein tyrosine phosphatase 1B contributes to leptin resistance with age. Endocrinology148433440. (doi:10.1210/en.2006-0672)

MussoCCochranEJavorEYoungJDepaoliAMGordenP2005The long-term effect of recombinant methionyl human leptin therapy on hyperandrogenism and menstrual function in female and pituitary function in male and female hypoleptinemic lipodystrophic patients. Metabolism54255263. (doi:10.1016/j.metabol.2004.08.021)

NaefLWoodsideB2007Prolactin/leptin interactions in the control of food intake in rats. Endocrinology14859775983. (doi:10.1210/en.2007-0442)

NagyGSTsiodrasSMartinLDAvihingsanonAGavrilaAHsuWCKarchmerAWMantzorosCS2003Human immunodeficiency virus type 1-related lipoatrophy and lipohypertrophy are associated with serum concentrations of leptin. Clinical Infectious Diseases36795802. (doi:10.1086/367859)

NavarroVMRuiz-PinoFSanchez-GarridoMAGarcia-GalianoDHobbsSJManfredi-LozanoMLeonSSangiao-AlvarellosSCastellanoJMCliftonDK2012Role of neurokinin B in the control of female puberty and its modulation by metabolic status. Journal of Neuroscience3223882397. (doi:10.1523/JNEUROSCI.4288-11.2012)

OzataMOzdemirICLicinioJ1999Human leptin deficiency caused by a missense mutation: multiple endocrine defects, decreased sympathetic tone, and immune system dysfunction indicate new targets for leptin action, greater central than peripheral resistance to the effects of leptin, and spontaneous correction of leptin-mediated defects. Journal of Clinical Endocrinology and Metabolism8436863695. (doi:10.1210/jcem.84.10.5999)

OzcanLErginASLuAChungJSarkarSNieDMyersMGJrOzcanU2009Endoplasmic reticulum stress plays a central role in development of leptin resistance. Cell Metabolism93551. (doi:10.1016/j.cmet.2008.12.004)

PardiniVCVictoriaIMRochaSMAndradeDGRochaAMPieroniFBMilagresGPurischSVelhoG1998Leptin levels, β-cell function, and insulin sensitivity in families with congenital and acquired generalized lipoatropic diabetes. Journal of Clinical Endocrinology and Metabolism83503508. (doi:10.1210/jcem.83.2.4567)

PehlivanovBMitkovM2009Serum leptin levels correlate with clinical and biochemical indices of insulin resistance in women with polycystic ovary syndrome. European Journal of Contraception and Reproductive Health Care14153159. (doi:10.1080/13625180802549962)

PinillaLAguilarEDieguezCMillarRPTena-SempereM2012Kisspeptins and reproduction: physiological roles and regulatory mechanisms. Physiological Reviews9212351316. (doi:10.1152/physrev.00037.2010)

PintoSRoseberryAGLiuHDianoSShanabroughMCaiXFriedmanJMHorvathTL2004Rapid rewiring of arcuate nucleus feeding circuits by leptin. Science304110115. (doi:10.1126/science.1089459)

PirwanyIRFlemingRSattarNGreerIAWallaceAM2001Circulating leptin concentrations and ovarian function in polycystic ovary syndrome. European Journal of Endocrinology145289294. (doi:10.1530/eje.0.1450289)

QuennellJHMulliganACTupsALiuXPhippsSJKempCJHerbisonAEGrattanDRAndersonGM2009Leptin indirectly regulates gonadotropin-releasing hormone neuronal function. Endocrinology15028052812. (doi:10.1210/en.2008-1693)

Ramlau-HansenCHThulstrupAMNohrEABondeJPSorensenTIOlsenJ2007Subfecundity in overweight and obese couples. Human Reproduction2216341637. (doi:10.1093/humrep/dem035)

ReindollarRHNovakMThoSPMcDonoughPG1986Adult-onset amenorrhea: a study of 262 patients. American Journal of Obstetrics and Gynecology155531543. (doi:10.1016/0002-9378(86)90274-7)

ReznikovAGMcCannSM1993Effects of neuropeptide Y on gonadotropin and prolactin release in normal, castrated or flutamide-treated male rats. Neuroendocrinology5711481154. (doi:10.1159/000126481)

RoaJGarcia-GalianoDVarelaLSanchez-GarridoMAPinedaRCastellanoJMRuiz-PinoFRomeroMAguilarELopezM2009The mammalian target of rapamycin as novel central regulator of puberty onset via modulation of hypothalamic Kiss1 system. Endocrinology15050165026. (doi:10.1210/en.2009-0096)

RomualdiDCampagnaGSelvaggiLJrCentoRProtoCLanzoneAGuidoM2008Metformin treatment does not affect total leptin levels and free leptin index in obese patients with polycystic ovary syndrome. Fertility and Sterility8912731276. (doi:10.1016/j.fertnstert.2007.05.004)

RosenbaumMLeibelRL1999Clinical review 107: role of gonadal steroids in the sexual dimorphisms in body composition and circulating concentrations of leptin. Journal of Clinical Endocrinology and Metabolism8417841789. (doi:10.1210/jcem.84.6.5787)

SabatinoFDCollinsPMcDonaldJK1989Neuropeptide-Y stimulation of luteinizing hormone-releasing hormone secretion from the median eminence in vitro by estrogen-dependent and extracellular Ca2+-independent mechanisms. Endocrinology12420892098. (doi:10.1210/endo-124-5-2089)

SadagurskiMLeshanRLPattersonCRozzoAKuznetsovaASkorupskiJJonesJCDepinhoRAMyersMGJrWhiteMF2012IRS2, signaling in LepR-b neurons suppresses FoxO1 to control energy balance independently of leptin action. Cell Metabolism15703712. (doi:10.1016/j.cmet.2012.04.011)

Sanchez-GarridoMATena-SempereM2013Metabolic control of puberty: roles of leptin and kisspeptins. Hormones and Behavior64187194. (doi:10.1016/j.yhbeh.2013.01.014)

SchiothHBKakizakiYKohsakaASudaTWatanobeH2001Agouti-related peptide prevents steroid-induced luteinizing hormone and prolactin surges in female rats. Neuroreport12687690. (doi:10.1097/00001756-200103260-00014)

von SchnurbeinJMossANagelSAMuehlederHDebatinKMFarooqiISWabitschM2012Leptin substitution results in the induction of menstrual cycles in an adolescent with leptin deficiency and hypogonadotropic hypogonadism. Hormone Research in Paediatrics77127133. (doi:10.1159/000336003)

SchubringCEnglaroPSieblerTBlumWFDemirakcaTKratzschJKiessW1998Longitudinal analysis of maternal serum leptin levels during pregnancy, at birth and up to six weeks after birth: relation to body mass index, skinfolds, sex steroids and umbilical cord blood leptin levels. Hormone Research50276283. (doi:10.1159/000023290)

SeeberRMSmithJTWaddellBJ2002Plasma leptin-binding activity and hypothalamic leptin receptor expression during pregnancy and lactation in the rat. Biological Reproduction6617621767. (doi:10.1095/biolreprod66.6.1762)

SienkiewiczEMagkosFAronisKNBrinkoetterMChamberlandJPChouSArampatziKMGaoCKoniarisAMantzorosCS2011Long-term metreleptin treatment increases bone mineral density and content at the lumbar spine of lean hypoleptinemic women. Metabolism6012111221. (doi:10.1016/j.metabol.2011.05.016)

Sir-PetermannTPiwonkaVPerezFMaliqueoMRecabarrenSEWildtL1999Are circulating leptin and luteinizing hormone synchronized in patients with polycystic ovary syndrome?Human Reproduction1414351439. (doi:10.1093/humrep/14.6.1435)

SoyupekSArmaganASerelTAHoscanMBPerkHKaraozECandirO2005Leptin expression in the testicular tissue of fertile and infertile men. Archives of Andrology51239246. (doi:10.1080/01485010590919666)

TeerdsKJde RooijDGKeijerJ2011Functional relationship between obesity and male reproduction: from humans to animal models. Human Reproduction Update17667683. (doi:10.1093/humupd/dmr017)

Tena-SempereM2007Roles of ghrelin and leptin in the control of reproductive function. Neuroendocrinology86229241. (doi:10.1159/000108410)

Tena-SempereMPinillaLGonzalezLCDieguezCCasanuevaFFAguilarE1999Leptin inhibits testosterone secretion from adult rat testis in vitro. Journal of Endocrinology161211218. (doi:10.1677/joe.0.1610211)

Tena-SempereMPinillaLGonzalezLCNavarroJDieguezCCasanuevaFFAguilarE2000In vitro pituitary and testicular effects of the leptin-related synthetic peptide leptin(116–130) amide involve actions both similar to and distinct from those of the native leptin molecule in the adult rat. European Journal of Endocrinology142406410. (doi:10.1530/eje.0.1420406)

TessierDRFerraroZMGruslinA2013Role of leptin in pregnancy: consequences of maternal obesity. Placenta34205211. (doi:10.1016/j.placenta.2012.11.035)

TfayliHUlnachJWLeeSSutton-TyrrellKArslanianS2011Drospirenone/ethinyl estradiol versus rosiglitazone treatment in overweight adolescents with polycystic ovary syndrome: comparison of metabolic, hormonal, and cardiovascular risk factors. Journal of Clinical Endocrinology and Metabolism9613111319. (doi:10.1210/jc.2010-2547)

ThongFSMcLeanCGrahamTE2000Plasma leptin in female athletes: relationship with body fat, reproductive, nutritional, and endocrine factors. Journal of Applied Physiology8820372044.

TortorielloDVMcMinnJChuaSC2004Dietary-induced obesity and hypothalamic infertility in female DBA/2J mice. Endocrinology14512381247. (doi:10.1210/en.2003-1406)

UrbanJHDasILevineJE1996Steroid modulation of neuropeptide Y-induced luteinizing hormone releasing hormone release from median eminence fragments from male rats. Neuroendocrinology63112119. (doi:10.1159/000126947)

VulliemozNRXiaoEXia-ZhangLWardlawSLFerinM2005Central infusion of agouti-related peptide suppresses pulsatile luteinizing hormone release in the ovariectomized rhesus monkey. Endocrinology146784789. (doi:10.1210/en.2004-1093)

WaltersKAAllanCMHandelsmanDJ2012Rodent models for human polycystic ovary syndrome. Biological Reproduction149112. (doi:10.1095/biolreprod.111.097808)

WangMYChenLClarkGOLeeYStevensRDIlkayevaORWennerBRBainJRCharronMJNewgardCB2010Leptin therapy in insulin-deficient type I diabetes. PNAS10748134819. (doi:10.1073/pnas.0909422107)

WarrenMPVoussoughianFGeerEBHyleEPAdbergCLRamosRH1999Functional hypothalamic amenorrhea: hypoleptinemia and disordered eating. Journal of Clinical Endocrinology and Metabolism84873877. (doi:10.1210/jcem.84.3.5551)

WatanobeHSchiothHBWikbergJESudaT1999The melanocortin 4 receptor mediates leptin stimulation of luteinizing hormone and prolactin surges in steroid-primed ovariectomized rats. Biochemical and Biophysical Research Communications257860864. (doi:10.1006/bbrc.1999.0547)

WeltCKChanJLBullenJMurphyRSmithPDePaoliAMKaralisAMantzorosCS2004Recombinant human leptin in women with hypothalamic amenorrhea. New England Journal of Medicine351987997. (doi:10.1056/NEJMoa040388)

WhiteVGonzalezECapobiancoEPustovrhCMartinezNHigaRBaierMJawerbaumA2006Leptin modulates nitric oxide production and lipid metabolism in human placenta. Reproduction Fertility and Development18425432. (doi:10.1071/RD05105)

YannakouliaMYiannakourisNBluherSMatalasALKlimis-ZacasDMantzorosCS2003Body fat mass and macronutrient intake in relation to circulating soluble leptin receptor, free leptin index, adiponectin, and resistin concentrations in healthy humans. Journal of Clinical Endocrinology and Metabolism8817301736. (doi:10.1210/jc.2002-021604)

YildizhanRIlhanGAYildizhanBKolusariAAdaliEBugdayciG2011Serum retinol-binding protein 4, leptin, and plasma asymmetric dimethylarginine levels in obese and nonobese young women with polycystic ovary syndrome. Fertility and Sterility96246250. (doi:10.1016/j.fertnstert.2011.04.073)

YuWHKimuraMWalczewskaAKaranthSMcCannSM1997aRole of leptin in hypothalamic–pituitary function. PNAS9410231028. (doi:10.1073/pnas.94.3.1023)

YuWHWalczewskaAKaranthSMcCannSM1997bNitric oxide mediates leptin-induced luteinizing hormone-releasing hormone (LHRH) and LHRH and leptin-induced LH release from the pituitary gland. Endocrinology13850555058. (doi:10.1210/endo.138.11.5649)

Cited By

PubMed

Google Scholar