Yorkie Weight Loss The Link Between Weight and Reproductive Health

How Much Should My Yorkie Weigh?

Yorkshire terriers are prized for their courageous demeanor crammed into a small body. You may have the question arising in your brain, How Much Should My Yorkie Weigh? The answer isnt always to the point, and there are numerous factors that influence the size of a Yorkie. Genetics, nutrition, and overall health all play a part.

In this article, you will come across

• A Yorkie weight chart so you can keep track of your puppys development.
• Information on the average Yorkie weight.
• And much more

How Much Should Yorkies Weigh?

Yorkshire Terriers should weigh 7 pounds (3.18 kg) or less and of height between 7 and 8 inches (17.8 20.3 cm) tall at the withers (the ridge at the base of the neck, between the shoulder blades). These restrictions, however, do not apply to all Yorkies.

What Should Yorkies Weigh?

Ideally, Yorkshire Terriers should weigh 7 pounds (3.18 kg) or less and of height between 7 and 8 inches (17.8 20.3 cm) tall at the withers (the ridge at the base of the neck, between the shoulder blades).

You should keep in mind that the above-mentioned information may not be applied to all Yorkies. If you find your Yorkies weight to be too little or too much, its best to consult a vet.

Yorkshire terrier weight chart by age & weight

According to PetMD, you can compare your Yorkies weight using the following weight chart.

So, if your Yorkies birthweight is around 3 oz, then by the second week, as per the table, his weight should be 6 to 7 oz and by the tenth week, it should be 19 to 20 oz.

How Much Does A Teacup Yorkie Weigh?

A Teacup Yorkies average weight is 2 to 4 pounds, and its maximum height is 7 inches.

Teacup Yorkies are a miniature version of Yorkshire Terriers, as the name suggests. Due to their cuteness, they are popular among pet owners who enjoy small dogs or the so-called toy breed.

Teacup Yorkies are adorable pets with sweet personalities. Theyre also very compact, which is ideal if you only have a limited amount of space at home. You can keep your Teacup healthy for years with proper care and attention. The right supplements and food will also help your dogs overall health.

Teacups can easily fit in your hand or a small dog bag because they are so small. Many Teacup Yorkies are only 5 to 7 inches tall, making them perfect for cradling in your palm! Some owners will spend a small fortune grooming their dogs to make them look like teddy bears.

During the first 12 weeks of growth, depending on the size of your Teacup Yorkie at birth, it will gain 1 to 2 lbs and 2 to 3 inches, and 2 to 4 lbs and 5 to 6 inches by week 24. A full-grown Teacup Yorkie can weigh 2 to 4 pounds and stand 5 to 7 inches tall.

Also Read: What is the average lifespan of a Yorkie?

What Is The Average Size (Height) Of A Yorkie?

When measured from the ground to the ridge between their shoulder blades, fully grown Yorkshire Terriers are typically 7 to 8 inches (17.8 20.3 cm) tall. The length of a Yorkie should be roughly equal to their height (measured from the base of their neck to the base of their tail).

Yorkie sizes, on the other hand, can and do vary. Its not uncommon for siblings to have vastly different sizes. Birth weight, nutrition, and genetics all play a role in determining size differences.

Yorkies are small no matter where they fall on the spectrum, but if your Yorkie is much shorter than 7 inches (17.8 cm), you should ask your veterinarian to check for any health issues. Yorkies that are too small are prone to a number of health problems.

While there are larger purebred Yorkies out there, your dog may not be purebred if your Yorkie is over 8 inches tall.

What Is The Average Weight Of A Yorkie?

Yorkies usually weigh between 4 and 7 pounds (1.81 and 3.18 kilograms), though purebred Yorkies can weigh up to 10 pounds.

Also Read: When do yorkies stop growing?

According to Dr. Alison Colyer, DVM, there have also been reports of purebred Yorkies weighing more than 15 pounds, which is unusual. However, when Yorkies grow to be so large, its usually because a larger dog breed was introduced somewhere in their ancestry.

You shouldnt be concerned as long as your Yorkie is healthy and follows a balanced diet and gets plenty of exercises. The weight of Yorkies varies depending on their diet, exercise, and lifestyle. However, your Yorkie is considered underweight if it weighs less than 4 pounds (1.81kg) when fully grown.

Teacup Yorkies are Yorkies that weigh less than 4 pounds. These dogs are at risk of developing a variety of health issues.

How Much Should A Healthy Yorkie Weigh?

A healthy Yorkie should weigh around 4 to 6 pounds. However, it should weigh no more than 7 pounds.

If youre having trouble weighing your dog on a scale or arent sure if theyre the right

weight for their size, you can always do a visual or physical examination of their body.

Also Read: Best food for Yorkie puppy

How To Inspect The Weight Of Your Yorkie?

• To do a visual assessment, look down at your dog from behind. As you move your gaze from their ribcage to their waist, your dogs waist should gently curve inward. The curve inward will be sharp and noticeably smaller if your dog is underweight.
• You can also inspect your dogs abdomen by looking at its side profile. Your dogs abdomen will slope slightly upward from the rib cage if they are a healthy weight. A skinny dog will have no visible body fat and will have its stomach tucked sharply upward from the ribs.
• To check their weight, place your hands on the sides of their bodies, near the rib cage. Without being able to see them, you should be able to feel each rib. If you can see your dogs ribs, he or she is underweight. But, if you cant feel their ribs, theyre either overweight or in need of more exercise.

If the hair on your Yorkie prevents you from making a visual assessment, you can use your hand to look for obvious physical signs that your dog is overweight or underweight.

Run your fingers down your dogs spine and then feel for their pelvic bone to complete this assessment.

What Are the Signs That My Yorkie Is Overweight?

Each breed, like each person, is unique. So dont be alarmed if the number on the scale when you weigh your Yorkie at home appears to be quite large.

Instead, get out your calculator and do some math. Get a chart from your veterinarian or look it up online that shows your dogs ideal weight based on his breed, height, and age.

1. Comparatively Heavier Than The Usual Range

Your Yorkie is overweight if he is 5 to 19 percent heavier than he should be. A small change in his routine and diet can have a significant impact on his overall health, not just on the scale. If he is 20% heavier than normal, more drastic measures may be required.

Ideally, a Yorkie should weigh between four to seven pounds.

2. Rib Test

The rib test is a good indicator if youre not sure whether your Yorkie is overweight or not. Circumambulate his flanks and abdomen with your hands. You should be able to feel the ribs on a dog that is at its ideal weight (but not see them, which would mean your dog is too skinny). If you cant find them, if you cant feel them through your dogs fat, its time to change his diet and get him to exercise.

Also Read: Best dog food for yorkie

3. Lethargic and Lazy Behavior

Your Yorkie used to be incredibly energetic, to the point of depleting your own reserves. When he was a puppy, he used to play around, go fetch, be excited whenever you returned home, try to catch his tail, or, much to your dismay, try to chase bicycles and cars. He now prefers the comfort of his couch to play outside, and sleeping has gradually become more appealing.

If this sounds familiar, its possible that your Yorkie has become apathetic as a result of his weight, which prevents him from being active, or because exercising requires a lot more effort than it used to. Your dog will be exhausted if he is carrying too much weight. A general feeling of this laziness could indicate that your Yorkie is overweight.

Can A Yorkie Weigh 15 Pounds?

Though Yorkies should weigh 4 7 pounds, pet Yorkies can weigh up to 12 15 pounds.

If your Yorkie is 15 pounds, it doesnt always mean that he is overweight. If your four-legged friend is short and has a lot of body mass, it is a cause of concern, as the weight can be considered overweight.

However, a lean and tall Yorkie weighing 15 pounds is usually normal. Its best to do a quick rib test as discussed in the earlier sections to determine this.

How Big Is A Full Size Yorkie?

Yorkies are finished growing by the age of two, and their weight should not fluctuate much if they are fed a balanced, consistent diet.

When measured from the ground to the ridge between their shoulder blades, fully grown Yorkshire Terriers are typically 7 to 8 inches (17.8 20.3 cm) tall.

Theyll have formed a strong bond by this point, and they wont want to be left alone, so they may follow you around the house at times. Theyll act as a miniature guard dog, patrolling your home and alerting you to any unusual activity. Especially if its a pesky squirrel thats invading your yard!

Is A Large Yorkie Still Healthy?

When compared to other dog breeds, even large Yorkies are still small. If your Yorkie weighs more than 9 pounds but doesnt appear overweight and your veterinarian is unconcerned, you shouldnt be concerned.

According to Dr. Krista Williams, DVM, a Yorkies weight is determined by both their bone structure and their diet. Dogs that are taller and longer in stature will also weigh more. The amount they weigh will be determined by their stature and muscle mass.

Any dog can carry an excessive amount of weight. Yorkshire Terriers weighing more than 10 pounds should be examined to see if there is a need for weight loss or if excess fat is causing health problems.

What Problems Is An Overweight Yorkie Prone To?

If your Yorkie is overweight, he might have the below problems:

• Diabetes
• Skin issues
• Heart problems
• Joint problems
• Kidney defects
• Canine arthritis
• Liver-related issues
• Mobility and locomotive problems
• Breathing problems
• High blood pressure

How To Make Your Yorkie Lose Weight?

If you feel that your Yorkie is overweight, you can follow the below steps to control his weight:

• Fewer calories
• Increased physical activity
• Keeping them active
• Healthier diet
• Cut down carbs
• More fiber and veggies

How To Make Your Yorkie Gain Weight?

An underweight Yorkie, weighing less than 4 pounds is prone to diseases. Hence, it is important that you follow the below steps that will help him gain some weight.

• Avoid injuries
• High protein and fatty foods
• More exercise
• Feed fresh and wet foods
• Free feeding or small foods throughout the day

Obesity as disruptor of the female fertility

Major functions of the female gonads include the production of gametes, the oocytes, and sex hormones that control the development of the female secondary sexual characters and support the pregnancy. In physiology, these functions are cyclically exerted between puberty and menopause, and are regulated by endocrine and paracrine factors that interact with several cell types located in ovaries [1]. Thus, besides other pathological outcomes, dysfunctional or altered regulation of these mechanisms can either directly or indirectly result in infertility.

A number of factors appear to concur to provoke infertility in women mainly including ovulatory dysfunction, tubal, cervical and/or uterine factors, as well as endometriosis although 2030% of cases remain unexplained [4]. Recently, the effects of lifestyle on female reproductive health have received great attention as well as the body mass index (BMI), foods and nutrients, sport and physical activity, stressing jobs and other conditions, are currently widely claimed as having a negative impact on the female fertility [5].

Here, we critically review the potential influence of the altered metabolic state on the reproductive health of women, focusing the effects of obesity on fertility, and the management of infertility in obese and overweight women.

Molecular and endocrinological influence of obesity on woman fertility

In female mammals, a number of evolutionary mechanisms are enrolled to integrate environmental, nutritional and hormonal cues in order to guarantee reproduction in normal energetic conditions and, vice versa, to inhibit it in case of food scarcity. This metabolic strategy could be an advantage in nutritionally poor environments, but nowadays is affecting womens health since the energy states may influence the female reproductive health in conditions of under or overweight.

Obesity and strenuous physical activity are conditions that alter the profiles of specific hormones such as insulin and adipokines and, thus, definitely impair the women fertility. Furthermore, there is undoubtedly a tight interconnection between energy metabolism and fertility, above all in females.

Obesity is a common problem among women of reproductive age. Obesity and overweight involves an abnormal and excessive fat accumulation that negatively affects the health status. According to the World Health Organization (WHO), if BMI is equal or greater than 25kg/m², it is considered overweight, whereas the BMI higher than 30kg/m² defines obesity [19]. The WHO reports that 60% of women are overweight in the United States and in most European countries while 30% of the female population are obese. Moreover, 6% of all women are morbidly obese (BMI35kg/m²) [20]. The negative effects of obesity on the reproductive physiology are known, since obese women frequently undergo menstrual irregularity with ovulatory disorders, endometrial pathology, and infertility.

The impact of obesity on reproductive function, especially ovulatory disorders, are mainly attributable to endocrine mechanisms [21], which interfere with neuroendocrine and ovarian functions, and reduce the ovulation omeostatic [22]. In obese women, gonadotropin secretion is affected as effect of the increased peripheral aromatization of androgens to estrogens while the insulin resistance and hyperinsulinemia lead to hyperandrogenemia. Furthermore, the sex hormone-binding globulin (SHBG), growth hormone (GH), and insulin-like growth factor binding proteins (IGFBP) are decreased and leptin levels are increased. Thus, the neuroregulation of the hypothalamic-pituitary-ovarian (HPO) axis may be severely deranged while the obese condition also increases the risk of miscarriage, poor pregnancy outcomes, and impaired fetal well being [23].

The risk of infertility has been shown to be threefold higher in obese than in non-obese women, and several studies have demonstrated that the obese females need longer time to pregnancy. In particular, two studies performed in large cohorts of Danish women planning pregnancies showed an inverse relation of fecundity with respect to the BMI increase [24]. It is noteworthy that obese women remain subfertile even in the absence of ovulatory dysfunction and Gesink and coworkers showed reduced fecundity in eumenorrheic obese women by examining a large American cohort of more than 7000 women in whom the probability of spontaneous conception linearly declined with each BMI point >29kg/m² as in a parallel study completed in a Dutch cohort of more than 3000 women with normal cycles [25].

Moreover, fertility in obese women seems to be impaired also in assisted conception programs. In fact, overweight and obesity are also associated with negative outcomes for patients undergoing in vitro fertilization (IVF) due to the poor oocyte quality, as well as the lower preimplantation rate and uterine receptivity. Therefore, in these women it is strongly recommend the weight loss in order to improve the fertility functions [26].

The molecular and endocrinological aspects of obesity, its effects and consequences on the reproductive system as well as benefits from modifying lifestyles improving the reproductive outcomes, are next reviewed.

Adipokines as major fat tissue soluble products

The adipose tissue is considered an endocrine organ that plays important roles in the regulation of many physiological events, such as reproduction, immune response, glucose and lipid metabolism, through the secretion of a variety of bioactive cytokines, named adipokines, commonly involved in metabolic regulation and inflammatory processes.

During the last years, the dysfunction of the adipose tissue has been implicated in the pathophysiology of infertility based on recently discovered effects of adipokines. Their normal levels are critical to maintain the integrity of hypothalamus-pituitary-gonadal axis as well as to regulate ovulatory processes, successful embryo implantation, and in general the physiologic pregnancy.

The family of adipokines includes the adipose-specific cytokines, namely secreted by adipocytes, such as leptin, adiponectin (APN), resistin, visfatin and omentin, and the non adipose specific cytokines such as retinol binding protein-4 (RBP4), lipocalin-2 (LCN2), chemerin, interleukin 6 (IL6), interleukin 1 (IL1), and tumor necrosis factor (TNF). The panel of adipokines is depicted in Table .

Table 1

Major effects of adipokines in fertility of the obese woman

Abnormal levels of these factors have been shown to be strongly associated with both insulin resistance (IR) and type 2 diabetes mellitus (T2DM) and in patients with the PCOS, a severe dysfunction of adipose tissue has been observed leading to over-production of pro-inflammatory adipokines such as TNF and, concurrently, reduction of a few beneficial adipokines such as APN. Peculiarities of each bioactive cytokine are next summarized.

• Leptin-

  Leptin is a 167-amino acid protein encoded by the

  ob

  gene. It is an important hormone involved in the regulation of food intake, energy balance, and body weight. Leptin is the first discovered adipokine to realize the endocrine functions of adipose tissue Fig.. Its predominantly secreted by adipose tissue and largely available in many organs as stomach, placenta, hypothalamus, pituitary, and mammary gland. The leptin receptor (LEPR) is a single transmembrane domain receptor that is highly expressed in the choroid plexus. There are six isoforms of the LEPR (Ob-Ra, b, c, d, e, and f) due to the alternative RNA splicing. Leptin is constitutively secreted by adipocytes in relation to the extent of the adipose mass and is abundant in subjects with extensive abdominal fat. It suppresses the food intake and promotes energy expenditure mainly via its direct effects on hypothalamic neurons, and is thus considered an anti-obesity hormone. Its levels decrease with fasting and increase after food intake [

  27

  ].

  Functional properties of adipocites

Higher circulating levels of leptin may lead to chronic down-regulation of LEPR in the brain of obese women, and higher leptin-BMI ratios may well explain lower rates of pregnancy with IVF. Jain et al., found that the amplitude of LH pulsatility was significantly lower in eumenorrheic obese women, thus suggesting a central defect. Moreover, higher serum levels of leptin in obese women correlate with higher levels of leptin in the follicular fluid. In vitro studies have shown that leptin affects steroidogenic pathways in granulosa cells and decreases both estrogen and progesterone production in a dose-dependent manner [28]. This negative effect of obesity on the oocyte physiology could have downstream effects on endometrial receptivity and embryo implantation.

• Adiponectin- Adiponectin (APN) is the most abundant secreted protein expressed exclusively in adipose tissue. There are three forms of APN: at low molecular weight (APN-LMW); at medium molecular weight (APN-MMW); and at high molecular weight (APN-HMW). Three receptors have been thus identified for APN: AdipoR1, AdipoR2, and T-cadherin.

AdipoR1 and AdipoR2 receptors are ubiquitously expressed and largely on female reproductive tissues, including ovary, placenta, endometrium, and oviduct [29]. It has been shown that APN inhibits LH and GNRH release, indicating its possible role in modulating the central reproductive endocrine axis [30].

Circulating APN levels decrease with obesity and increase with weight loss and major effects of APN are devoted to increase the insulin sensitivity by stimulating glucose uptake in liver and muscles, while decreasing hepatic gluconeogenesis, and promoting the fatty acid -oxidation in the skeletal muscle. Consequently, APN reduces triglyceride (TG) accumulation and enhances the insulin sensitivity [31].

Reduced expression of AdipoR1 and AdipoR2 has been also observed in endometria of women with recurrent implantation failure compared with fertile women, suggesting an important role of APN signaling in uterine receptivity and its possible contribution to implantation failures and pregnancy loss in women with maternal metabolic conditions such as obesity and PCOS [32].

• Resistin-

  Resistin is a small cysteine-rich 94-amino acid polypeptide. This adipokine is considered a potential link between obesity and T2DM as result of its inhibitory effect on adipocyte differentiation and its association with IR. Resistin is mainly secreted by peripheral blood mononuclear cells including macrophages and by stromal cells in adipose tissue, but its mRNA has been also found in hypothalamus-pituitary axis [

  33

  ].

The resistin gene polymorphism is associated with BMI in women with PCOS, suggesting that it might be related to adiposity in PCOS. A randomized placebo-controlled study recently showed that treatment with the insulin sensitizer rosiglitazone significantly reduces the serum resistin levels in overweight women with PCOS, thus implying the contribution of this adipokine to the insulin sensitivity improvement during treatment [34]. In summary, resistin seems to be an important adipokine that is involved in obesity, IR, PCOS and endocrine dysfunction.

• Visfatin- Visfatin is a protein expressed by a variety of tissues and cell types, including adipocytes, lymphocytes, bone marrow, liver, muscle, trophoblast, and fetal membranes.

In vitro studies have demonstrated that visfatin stimulates the glucose uptake in both adipocytes and muscle cells while suppressing the release of glucose by hepatocytes. A recent meta-analysis revealed that plasma visfatin is significantly increased in both overweight and obese subjects, or in patients with T2DM and metabolic syndrome [35]. It has been also reported that the gene expression and the circulating levels of visfatin are increased in women with PCOS as compared with age and BMI matched controls. A positive correlation, however, has been found between plasma visfatin concentration and fasting insulin in a homeostasis model assessment (HOMA)-IR [36].

• Omentin- Omentin-1, also named intelectin-1, a 313-amino acid peptide, is an anti-inflammatory adipokine preferentially expressed in stromal vascular cells of visceral adipose tissue. It is suggested that this substance makes an important contribution to the physiological difference between visceral and subcutaneous adipose tissue. It is also abundant in vasculature, small intestine, colon, thymus and heart.

Omentin-1 is the major circulating form but other homologues are known. Genes of both omentin-1 and omentin-2 are located as adjacent to each other at 1q22-q23, exactly in the region linked to type 2 diabetes mellitus. Both omentin homologues as circulating forms correlate with expression in visceral fat tissue [37]. Omentin-1 increases the insulin signal transduction as well as the insulin-stimulated glucose transport in human adipocytes though with no effect on basal glucose uptake, and contributes to the regulation of lipid metabolism. Its role, however, in the reproductions physiology is unclear.

Dysendocrine effects of obesity: hyper- and hypo-androgenism

• Obesity, hyperandrogenism and anovulation - Obesity, body fat location as upper versus lower body disposition, and muscle mass have important effects on the reproductive function and fertility. The majority of obese women have normal ovulatory menstrual cycles, remain fertile and have no apparent hyperandrogenism thus suggesting that obesity per se is not the only factor involved in the genesis of hyperandrogenism and ovulatory dysfunction. However, elevated androgen levels in obese women appear to be a common finding in the presence of amenorrhea. The mechanism by which the excess adipose tissue can be associated with hyperandrogenism remains controversial although the hyperinsulinemia plays a primary role in influencing obesity in hyperandrogenism.

Hyperinsulinemia and insulin resistance are the underlying causes that lead to obesity, accompanied by hyperandrogenism and alterations in steroidogenesis, in those patients with stromal hyperplasia of the ovaries. Both hyperinsulinemia and hyperandrogenism affect the ovarian function in both obese and non-obese women although the mechanism by which how hyperandrogenism and/or hyperinsulinemia inhibit the regular ovulation has not been fully understood. It has been experimentally shown that insulin has specific actions on steroidogenesis through its own receptor since it stimulates the theca cells to produce androgens and exert a growth stimulatory effect on stromal cells, thus priming the production of extradiol [38] Fig.. Another proposed mechanism of hyperandrogenism induced by hyperinsulinemia, which can be found in the PCOS patient obese or not, occurs through the insulin-like growth factor-I (IGF-I) which is secreted by human ovarian tissue while its receptors are also located in ovaries.

Pathophysioly of insuline resistance. This figure illustrates the complex interactions underlying the pathophysiology of PCOS. Insulin resistance and the resulting hyperinsulinemia are responsible for the majority of the changes found in PCOS. Insulin resistance in PCOS does not occur in all tissues, but rather appears to be tissue-specific. Skeletal-muscle and adipose tissue become insulin resistance resulting in decrease glucose uptake and increased lipolysis, respectively, whereas the ovary, adrenal and liver remain insulin sensitive. In PCOS, hyperinsulinemia occurs as a compensatory response to insulin resistance. This resulting hyperinsulinemia has a stimulatory effect on the ovaries and adrenal glands that leads to enhanced androgen production by these organs. More specifically, excess insulin enhances androgen production in ovarian theca cells in response to luteinizing hormone (LH) stimulation, resulting in follicular arrest and anovulation. In contrast hyperinsulinemia acts to suppress hepatic production of sex hormone-binding globulin (SHBG), the primary binding protein for testosterone in the serum. Therefore, insuline resistance whith compensatory hyperinsulinemia results in hyperandrogenemia

Insulin can bind IGF-I receptors (IGF-IR) as well as its own receptors and activates the tyrosine kinase of the -subunit resulting in triggering the intracellular events that potentiate those normally mediated by IGF-I. Therefore, the insulin-like growth factor binding proteins (IGFBP) include a group of secreted proteins which bind to IGF-I and IGF-II with high affinity and modulate the biological actions of IGF [38]. When the IGFBPs bind and activate the IGF-IR, the hepatic synthesis of IGFBP-I is decreased thus making IGF-I more biologically available with the final effect of enhancing the androgen production by theca interstitial and stromal cells Fig..

Insulin receptor tyrosine kinases. The subunit binds insulin and the transmits a signal from bound insulin to the cytoplasm. The insulin signal activates the receptors protein kinases domain in the cytoplasm. Proteine kinases from the receptor phosphorylate insuline-responsesubstrates triggering other chemical responses inside the cell. When IGFBPs binds and therefore activates the IGF-Ir, the hepatic synthesis of IGFBP-I is decreased, making IGF-I more biologically available, thus enhancing androgen production by theca interstitial and stromal cells

Willis et al., showed that insulin also reinforces the activity of the LH on granulosa cells by exerting two distinct effects on the preovulatory follicle, namely the steroidogenesis activation and the inhibition of mitosis thus restraining the terminal differentiation of those cells [39]. As a result of the enhanced steroidogenesis due to insulin and its interaction with LH, the unfavorable milieu produces the blockage of the follicle growth. Thus, the premature luteinization and the consequent follicular arrest result in menstrual cycle disorders and oligo-anovulation which appears strictly related to the obesity [40]. The increased estrogen production, due to peripheral conversion, impairs the function of HPG axis and renders both estrogen excess and hyperandrogenism as major causes of anovulation in these patients.

A nature-experiment of the association obesity/infertility is related to the Laron syndrome (LS), a rare autosomal recessively inherited disease described in consanguineous families originating from Mediterranean, middle-east or south Asian regions [41]. This syndrome is characterized by a primary GH insensitivity or resistance caused by deletions or mutations in the GH receptor gene, which leads to absence of GH activity and congenital IGF-I deficiency [42]. However, one of the intriguing characteristics of LS, in addition to dwarfism, is the chronic obesity which occurs in early childhood and does not decrease with long-term IGF-I treatment. In parallel with a remarkable increase of both subcutaneous and visceral fat, the majority of patients with LS progressively develop signs of metabolic syndrome as hyperlipidemia and non-alcoholic fatty liver disease. Based on this deeply altered metabolism of lipids, the women with LS are usually subfertile and require a treatment to induce ovulation for the chronic defects in their reproductive function [43]. Therefore, given the tight interconnection between energy metabolism and reproduction, the impact that obesity induces on fertility in these women can be considered an aggravating factor in this clinical condition.

• Obesity, menstrual cycle and fertility in hypoandrogenic women - Whether most of the studies on menstrual cycle and fertility in obesity have been completed in hyperandrogenic women, very few studies examined women without hyperandrogenism and/or with normal menstrual cycle.

One cross-sectional study performed in more than 250 overweight and obese non-hyper-androgenic women partially claiming problems of infertility, showed that 64% of these women were eumenorrheic with normal menstrual cycles, whereas in the original population 21% of them had oligomenorrhea and only 14% were hyper or polimenorrheic, thus proving that oligomenorrhea is the most frequent alteration of menstrual cycle in apparently fertile obese women [44].

The same study showed that abdominal fat accumulation measured by waist circumference, is the most predictive parameter of oligomenorrhea in apparently fertile women, independently from hyperinsulinemia, insulin resistance or other parameters. However, obese non-hyperandrogenic women, even with normal menstrual cycles and apparent normal fertility, have lower circulating levels of gonadotropins, estradiol and inhibin during the follicular phase, thus suggesting an inhibitory effect of obesity per se on the production of these hormones [45]. By contrast, the number of ovary follicles does not seem to be influenced by insulin and body mass in these patients 46].

Lastly, free testosterone (FT) levels are usually higher in obese premenopausal women without hyrsutism and normal/lower circulating levels of other androgens including dehidro-epiandrosterone (DHEA), DHEA-sulphate, androstenedione and 17-OH-progesterone [46], raising the possibility that increased concentrations of FT may have a negative effect on fertility. DHEA is a hormone intermediary in the testosterone- and estrogen-pathway. Its plasma levels are significantly lower in morbid obesity [47], and are inversely correlated with total body fat. These relationships might be the expression of a lower production of DHEA by adrenal glands and/or of higher DHEA uptake in adipose tissue, as well as of a lipomobilizing effect of DHEA. On the other hand, this hormone stimulates resting metabolic rate (RMR) and lipid oxidation at the level of visceral adipose tissue in particular, and enhances the glucose disposal by increasing the expression of GLUT-1 and GLUT-4 on fat cell plasma membrane [48]. For these reasons several IVF units administer DHEA to improve the endocrine environment and the influences on the oocytes.

Therefore, on the basis of these information, it is evident that the decrease of DHEA levels may furtherly enhance the fat accumulation, thus generating a vicious circle in obesity and contributing to higher insulin concentrations and lower fertility in obese women.

Obesity effects on reproduction apparatus

Obesity may affect the woman fertility by a number of events as impairment of ovarian follicles development, qualitative and quantitative defects of oocyte maturation, altered fertilization, disrupted meiosis and mitochondrial dynamics derangements leading to abnormal embryo preimplantation [49]. The excess of free fatty acids may exert a toxic effect in reproductive tissues producing a persistent cell damage and a chronic low-grade inflammatory state. To this regard, several mechanisms have been postulated to explain why obesity and/or the overweight affect the quality of female gametes and several hypotheses are related to plasmatic levels of reproductive hormones and their metabolism.

In this contest, Machtinger et al., explored the oocytes failed to be fertilized in IVF cycles of morbidly obese women, and described disarrayed meiotic spindles with misaligned metaphase chromosomes [50]. Independently from aneuploidy, obesity also appears to alter the mitochondrial function in the oocyte. One potential mechanism for oocyte organelle damage in obesity is the lipotoxicity. In fact, the excess fatty acids obtained from the diet can be stored as triglycerides in adipocytes although they are apparently unable to induce the cellular damage in this storage compartment. However, when this capacity is overwhelmed with continued dietary excess, fatty acids accumulate in other tissues and exert their toxic effects known as lipotoxicity [51].

Furthermore, obese women have higher levels of circulating free fatty acids, which damage non adipose cells by increasing reactive oxygen species (ROS) that, in turn, induce mitochondrial and ER stress resulting in apoptosis of multiple cell types including oocytes [52]. This effect is related to the chronic low grade inflammatory state related to obesity which is proven by the increased circulating levels of C-reactive protein (CRP), as well as lactate and triglyceride concentrations in follicular fluid, and by the enhanced expression of pro-inflammatory (CXCL2) and oxidative stress related (DUSP) genes [53].

The preimplantation embryo is also affected by the endometrial obese environment. Comparison of human IVF cycles with autologous oocytes show that obese women are more likely to create poor quality embryos [54] as effect of the lipotoxicity of embryonic cells in a similar fashion as described for the oocyte. However, there are conflicting data as to whether obesity has a significant effect on the endometrium. Although many factors contribute to restrain reproductive outcomes in obese women, Rhee JS et al., in their study emphasize the importance of decidualization defects in obese women which would alter the endometrial receptivity resulting in poor implantation [55].

The at risk fertility in obese women

Although in a high percentage of obese women the pregnancy occurs with normal accomplishment, several risks in their conception plans need to be considered and are briefly discussed.

Impact on egg viability and quality

The constitutive ovarian reserve in fertile women is not unlimited and the number of maturing oocytes usually declines with aging. For this reason, the impact of maternal environment and obesity on the differentiation of these cells is particularly consequential and negative environmental exposures may affect the developmental competence of the oocyte, defined as the ability of mature oocytes to be fertilized and support the embryo development [56]. Thus, based on the systemic inflammatory state associated to the obesity, the oocyte maturation is variably affected by the altered balance of driver hormones as SHBG with other soluble factors including insulin, glucose, lactate, triglycerides, and C reactive protein [53].

High BMI values also alter the concentration of certain adipokines. In rodent models, high concentrations of leptin impair the follicle development, ovulation, and oocyte maturation [57], whereas leptin deficient mice (ob/ob) are the animal experimental model to investigate the effects of obesity, and female ob/ob mice develop low numbers of antral follicules resulting in impaired folliculogenesis, reduced ovulation rate, and accelerated apoptosis of granulosa cells [58].

Furthermore, elevated levels of leptin associated with high BMI also impairs the steroidogenesis. The mechanisms by which leptin regulates the steroidogenesis in human granulosa cells have been investigated by Lin Q. et al., in experimental studies completed in 40 granulosa cell lines obtained from explanted human granulosa samples during in vitro fertilization program [59]. They show that human granulosa cells after exposure to high dosage of recombinant human leptin, inhibit 8-bromo cAMP-stimulated progesterone production in a dose-dependent manner with downregulation of StAR mRNA levels, a steroidogenic regulatory protein, produced for the progesterone synthesis. Therefore, they suggest that leptin interferes with the secretion of gonadotropin-stimulated proge-sterone in these cells and with induction of StAR protein by cAMP which, thus, is significantly reduced. They also proved that both cAMP-regulated steroidogenic enzymes and progesterone production could be inhibited by leptin via the MAPK pathway. These results confirm that leptin acts through its receptor to initiate the MAPK pathway and downregulates the cAMP-induced steroidogenesis in human granulosa cells [59].

Leptin receptors are structurally similar to the class I cytokine receptor family [53]. In humans, the leptin receptor (OB-R) is produced in several alternatively spliced forms, designated OB-Ra, OB-Rb, OB-Rc, OB-Re [60]. Each of these isoforms shows an extracellular domain and a transmembrane domain in common, with a variable intracellular domain typical for each isoform. Based on the variable intracellular domain, these isoforms are classified as short (OB-Ra), long (OB-Rb) and secreted (OB-Re) leptin receptor. Other than the classical JAK/STAT signalling pathways, leptin may act through OB-Ra or OB-Rb to trigger the MAPK cascade in two different ways, namely via tyrosine phosphorylation of JAK2 receptor-associated activation, or independently from the receptor phosphorylation [61]. Thus, the stimulation of granulosa cells by leptin was used to investigate the activation of MAPK pathway suggesting that MAPK cascades are involved in leptin mediated inhibition of steroidogenesis in granulosa cells by the phosphorylation of ERK, p38 and JNK.

Adiponectin is primarily secreted by adipocytes, but its serum levels drop down in obesity and in insulin resistance while increasing with weight loss [62]. It has been demonstrated that in obese women where circulating levels are lower, there would just reflect the insulin sensitivity and that this effect may negatively influence the control of ovulation since adiponectin is variably detectable in ovaries, follicular fluid, oocyte, corpus luteum, theca cells, while is weakly expressed by granulosa cells [63]. However, the direct effect of adiponectin in ovarian function remains unclear. In animal models, the protein has been described to influence both folliculogenesis and the follicular remodelling as well as to modulate the sex steroid secretion via activation of its own receptors R1 and R2, and by modulating the insulin/IGF system [64].

Ledoux and co-workers examined the effects of recombinant porcine adiponectin on porcine ovarian granulosa cells in vitro and demonstrated that the protein at physiologically levels equal to 1025g/ml, provokes expression of genes committed to the periovulatory remodelling of the ovarian follicle over a time frame of 6-24h. These include cyclooxygenase-2, prostaglandin E synthase, and vascular endothelial growth factor. Therefore, adiponectin modulates steroid synthetic protein gene expression by increasing the steroidogenic acute regulatory protein transcript and, concurrently, by reducing the cytochrome P450 aromatase. Finally, these studies demonstrated that the MAPK pathway, via phosphorylation of ERK1/2, is involved in mediation of the adiponectin signal in ovarian granulosa cells, rather than the protein kinase A, or the classic adiponectin transducer AMP-activated protein kinase. These results suggested that since adiponectin synthesis is reduced in obesity, this defect may play a substantial role in obesity-related ovarian dysfunction [64].

Other adipokines such as interluekin-6 (IL6), plasminogen activator inhibitor (PAI) type-1, or TNF family members may affect oocyte competence or maturation through alterations in steroidogenesis and interaction with other metabolic hormones [65]. While the mechanisms by which adipokines impact the oocyte quality have not been elucidated yet, their altered concentrations due to obesity represent the major potential factor by which obesity may negatively impact on the oocyte health thus affecting the fertility in women.

Obesity and miscarriage rate

The association between obesity and miscarriage has been assessed in a number of studies in both natural and assisted conceptions in which the miscarriage risk was as high as up to approximately 40% in obese women with respect to less than 15% in females with a normal BMI. However, despite these findings, there is no consensus about the causative mechanisms in obese women [66].

A major pathogenic factor could be related to the impaired stromal decidualization in obese women which is responsible of placental abnormalities, stillbirth and preeclampsia [67], although the most frequent cause of first trimester miscarriages usually related to embryo chromosomal pathologies, does not seem to be increased in overweight women [68].

AMH in obese patients

Anti-Mullerian hormone (AMH) is a product of the granulosa cells of small antral and pre-antral follicles, and clinically, it may be reflective of the prediction of ovarian reserve in women undergoing fertility evaluation and treatment [69]. For this reason, is important to evaluate the change in the levels of AMH, as a fertility parameter in obese women with or without PCOS, submitted to aerobic exercise with the aim of losing weight. The slimming via exercise or diet is considered one of the most important targets in lifestyle modification programmes capable to induce an improvement in reproductive function among obese women with PCOS [70]. Exercise interventions of moderate activity are one of the most important lifestyle modifications that positively influence on fertility and assisted reproductive technology outcomes [71].

Einas AE and coworkers, have studied the possible correlation with adiposity, clinical and hormonal parameters in PCOS and normo-ovulatory women, conducting a one-year study among obese women with or without polycystic ovary syndrome. All patients were classified into three age-matched groups; group A: controls, group B: PCOS patients and group C: obese women. The AMH, was measured at baseline and following 12weeks of supervised aerobic exercise. They conclude that the change in AMH levels correlated significantly with physical activity, therefore the authors claim that a moderate aerobic training for 12weeks had a positive significant effect on reproductive functions via modulating adiposity, AMH and fertility in obese women with or without PCOS [72].

Influence of obesity on fertility treatments

Overweight and obese women have lower outcomes following fertility treatments than normal population. They poorly respond to induction of ovulation, require higher doses of gonadotropins and longer treatment courses for follicular development and ovulatory cycles. In addition, the oocyte yield is lower in obese women resulting in a higher rate of cycle cancellation [73]. Ovarian stimulation for assisted reproduction produces fewer follicles leading to the harvest of fewer oocytes. Thus, the fertilization rates are scarce and the embryo quality is impaired in younger obese undergoing fertility treatments who definitely show low pregnancy rate with increased risk of early pregnancy loss.

Glueck CJ et al., report in their study that insulin sensitising-lowering agents ameliorate the reproductive, and metabolic disorders, typical of the obese patient [74]. The action of metformin is widely discussed in the literature, which is considered as the first-line medication for the treatment of type 2 diabetes. Women with PCOS receiving metformin improved pregnancy outcomes, and this has been attributed to its ability to reduce the insulin resistance as well as hyperinsulinaemia and the inhibitor of the hypofibrinolytic plasminogen activator resulting in improvement of oocyte quality and folliculogenesis for amelioration of PCOS.

The major effects of metformin include its property to decrease the liver glucose production by suppressing hepatic gluconeogenesis as well as the increase of insulin sensitivity and peripheral glucose uptake [75]_. The molecular mechanism of metformin is incompletely understood. Multiple potential mechanisms of action have been proposed, including; inhibition of the mitochondrial respiratory chain (complex I), activation of AMP-activated protein kinase (AMPK), inhibition of glucagon induced elevation of cyclic adenosine monophosphate (cAMP) with reduced activation of protein kinase A (PKA), inhibition of mitochondrial glycerophosphate dehydrogenase, and an effect on gut microbiota [76]. All these activities may have contributed to improve the oocyte maturation in PCOS and may exert a definitive favorable effect on infertility associated to inefficient oocyte differentiation and maturation.

Benefits from weight loss

Weight loss has been shown to improve reproductive outcomes by ameliorating fertility, as well as by regularizing menstrual cycles and increasing the chance of spontaneous ovulation and conception in anovulatory overweight and obese women.

Available data suggest that the weight loss equal to 5%10% of the body weight may definitely improve the fertility rate [77], whereas other studies prove that 5% of weight loss results in significant improvement of endocrine parameters, such as decrease of free testosterone, and LH and insulin levels, with the improvement of ovulation frequency [78].

Sim and collaborators investigated the effects of weight loss in overweight and/or obese women undergoing assisted reproductive procedures on their subsequent pregnancy outcome. In their observation, the weight loss achieved by diet and lifestyle change resulted in significantly increased pregnancy rates and/or live birth in overweight and/or obese women undergoing assisted reproductive technology (ART) in 8 of the 11 studies reviewed. In addition, regularization of the menstrual pattern, decrease in cancellation rates, increase in number of embryos available for transfer, reduction in the number of ART cycles required to achieve pregnancy, and a significant decrease in miscarriage rates were reported. Interestingly, an increase of the number of natural conceptions in five of the six studies was also reported [79].

However, the decision to postpone the treatment of fertility to allow weight loss often results in a further increase in maternal age in women who are not very young. A recent study demonstrated that the effect of BMI on IVF success was strongly influenced by age. In fact, the effect of BMI reduction alone is apparently reduced with increasing age, and in women aged 36yrs. or older, the weight loss may sometimes result not functional in favouring the woman fertility [80].