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Hormonal breast enhancement or augmentation is a highly experimental potential medical treatment for the breasts in which hormones or hormonal agents such as estrogen, progesterone, growth hormone (GH), and insulin-like growth factor 1 (IGF-1) are utilized or manipulated to produce breast enlargement in women.[1][2] It is a possible alternative or supplement to surgical breast augmentation with breast implants or fat transfer and other means of medical breast enlargement.[2]

In addition to pharmaceuticals, some herbal breast enlargement supplements contain phytoestrogens such as 8-prenylnaringenin (found in hops) and miroestrol (a constituent of Pueraria mirifica) and thus may be regarded as a form of hormonal breast enhancement.[3] However, evidence of their effectiveness, as well as safety data, are lacking.[3]

Breast growth

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See also: Breast development § Biochemistry

At puberty, estrogen, but not progesterone at this time, and GH/IGF-1 are critical in mediating the development of the breasts, and are synergistic in doing so.[4][5][6][7][8] In accordance, hormonal contraception and hormone replacement therapy (HRT) with estrogen (and/or progestogens) have been associated with increased breast growth and breast size.[9][10] Moreover, a trial of hormonal breast enhancement in 45 young women with very high doses (80 mg/injection) of intramuscular, bioidentical estrogen (in the form of estradiol polyphosphate, a slow-releasing estradiol prodrug) for six months found that only the women in whom an increase in IGF-1 levels occurred after four weeks (46.7% of subjects) experienced a significant increase in breast size (824.3 mm to 898.5 mm).[1][2] This is in accordance with the established fact that both estrogen and IGF-1 appear to be essential for breast development, and when present together, are synergistic in mediating it.[11][12]

The administration of estrogen to women with Turner syndrome, who normally do not develop breasts due to hypogonadism, results in normal pubertal breast development.[13] Estrogen and GH are often combined in Turner syndrome.[14][15] Estrogen in combination with GH or IGF-1 has been employed safely and effectively to improve bone density in women with anorexia nervosa.[16][17][18] Trans women who are treated with estrogen experience normal pubertal breast development similarly to the case of girls with Turner syndrome.[19] However, they generally show a smaller final breast size in comparison to their immediate relatives (one cup size less on average).[19] This is perhaps due to the fact that most trans women do not commence HRT until adulthood, which is of relevance because GH/IGF-1 levels significantly and progressively decrease after normal adolescent puberty (from late adolescence/early adulthood and thereafter).[20] As such, synergy of estrogen with GH/IGF-1, and by extension, maximal breast development potential, may be reduced.

Systemic administration of GH or IGF-1 causes mammary hyperplasia (enlargement of the mammary glands) in animals.[21] For example, in a study of aged female rhesus macaques, treatment with GH alone, IGF-1 alone, and the combination of GH and IGF-1, were found to produce mammary gland hyperplasia and increased mammary gland size and epithelial proliferation by 2-fold, 3- to 4-fold, and 4- to 5-fold, respectively, changes that were directly correlated with serum concentrations of GH and IGF-1.[22][23][24] Accordingly, research has found that girls with growth hormone deficiency (GHD) who are treated with GH experience accelerated breast growth[25] and that boys with growth hormone deficiency treated with GH sometimes experience gynecomastia.[26] Moreover, IGF-1 levels and activity have been found to be correlated with breast volume in the female general population.[10]

In women with Laron syndrome, where the growth hormone receptor (GHR) is defective and insensitive to GH and serum IGF-1 levels are very low, puberty, including breast development, is delayed, although full sexual maturity is always eventually reached.[27] Moreover, breast development and size are normal (albeit delayed) in spite of GH/IGF-1 axis insufficiency, and in some the breasts may actually be large in relation to body size (which has been hypothesized to be due to increased secretion of prolactin caused by a drift phenomenon from somatomammotrophic cells in the pituitary gland with a high GH secretion).[27][28] An animal model of Laron syndrome, the GHR knockout mouse, shows severely impaired ductal outgrowth at 11 weeks of age.[29][30][31] However, by 15 weeks, ductal development has caught up with that of normal mice and the ducts have fully distributed throughout the mammary fat pad, although the ducts remain narrower than those of wild-type mice.[29][30][31] In any case, female GHR knockout mice can lactate normally.[29][31] As such, taken together, it is said that the phenotypes of women with Laron syndrome and GHR knockout mice are identical, with diminished body size and delayed sexual maturation accompanied by normal lactation.[29]

An adolescent Vietnamese girl with Laron syndrome who was treated with a high dosage of IGF-1 and a gonadotropin-releasing hormone analogue for 3–4 years paradoxically experienced isolated progression of breast development without any other pubertal changes in spite of estrogen levels in the low prepubertal range.[32] Noting that gynecomastia is a recognized complication of treatment with GH and IGF-1, the authors of the study attributed the breast development to a synergism of her high, supraphysiological IGF-1 levels with the low levels of estrogen derived from peripheral aromatization of adrenal androgens.[32]

Certain long-acting growth hormone secretagogues, such as CJC-1295[33] and ibutamoren (MK-677),[34] are capable of reliably and effectively increasing serum GH and IGF-1 concentrations in humans.[35][36][37] Alternatively, exogenous, pharmaceutical GH and IGF-1 (as mecasermin or mecasermin rinfabate) themselves, or analogues of IGF-1 such as des(1-3)IGF-1 and IGF-1 LR3, may be employed to increase GH/IGF-1 axis function. A number of dietary supplements, including L-arginine, L-ornithine, L-lysine, acetyl-L-carnitine, and creatine, may be able to significantly increase GH levels, although evidence is mixed.[38][39][40][41][42] Vitamin D has been found to increase IGF-1 levels in both healthy subjects and individuals with GHD, and vitamin D deficiency is associated with low IGF-1 levels.[43][44][45] However, there is evidence that vitamin D may also potently inhibit breast growth via activation of the vitamin D receptor.[46][47][48][49]

Oral estrogen treatment suppresses IGF-1 production in the liver, where approximately 80% of serum IGF-1 originates from,[50] and reduces total serum IGF-1 levels (by 15–40%, dependent on dose and type of estrogen administered), as well as increases levels of insulin-like growth factor-binding protein 1 (IGFBP1) (a carrier protein that inhibits IGF-1 binding/activity).[51] This results in a state of functional GH resistance (as GH induces IGF-1 production and secretion in the liver to mediate most of its effects),[50] with combined oral estrogen and GH being less effective in evoking the clinical effects of GH relative to GH alone in clinical studies of individuals with hypopituitarism/GHD.[51] In contrast, treatment with combined GH and transdermal estrogen has been found not to decrease IGF-1 levels or increase IGFBP1 levels.[51] As such, estrogen administered via other routes of administration that bypass the liver, such as transdermal (in the form of estrogen patches), sublingual, intranasal, intramuscular injection, and subcutaneous injection, may be significantly more effective than oral estrogen.[51]

Progesterone and non-androgenic progestins, such as dydrogesterone, do not affect serum IGF-1 levels regardless of route of administration.[52] However, androgenic progestins, such as 19-nortestosterone derivatives like norethisterone and levonorgestrel and others like, to a lesser extent, medroxyprogesterone acetate (MPA), when taken orally, induce IGF-1 production via activation of the androgen receptor (AR) in the liver.[52] However, at the same time, androgens potently inhibit estrogen action on the breast, such as by suppressing ER expression in breast tissue, and this action would be expected to likely cancel out any benefit.[53][54] In accordance, a single small clinical study found that the addition of oral MPA to estrogen in trans women undergoing sex reassignment therapy did not result in increased breast size.[55]

Diet and nutrition have been found to affect serum IGF-1 levels. Specifically, low protein intake, fasting, and malnourishment are associated with low IGF-1 levels, whereas obesity is associated with high or normal IGF-1 levels and lowered IGFBP1 and IGFBP3 levels (resulting in higher free IGF-1 concentrations).[56][57][58] In addition, milk consumption and circulating IGF-1 levels have been found to be positively correlated.[59] Aside from diet and nutrition, exercise has also been found to significantly increase GH levels.[38]

Androgens, such as testosterone and dihydrotestosterone (DHT), powerfully suppress the action of estrogen in the breasts.[53][54][60][61] At least one way that they do this is by reducing the expression of the estrogen receptor in breast tissue.[53][54] In women with complete androgen insensitivity syndrome (CAIS), who are completely insensitive to androgens and have only modest levels of estrogen (50 pg/ml), the relatively low levels of estrogen are capable of mediating significant breast development, and the breast sizes of CAIS women, on average, are in fact actually larger than those of non-CAIS women.[60] In males treated with antiandrogens, gynecomastia (enlargement of the breasts in males) and mastodynia (breast tenderness/pain) commonly occur.[62][63][64] Antiandrogens, for instance spironolactone, are also known to cause breast enlargement and mastodynia in women.[65] Some examples of widely used and highly-potent antiandrogens include cyproterone acetate and bicalutamide.[66][67]

Cyclooxygenase-2 (COX-2) overexpression in mammary gland tissue produces mammary gland hyperplasia as well as precocious mammary gland development in female mice, indicating a strong stimulatory effect of this enzyme on the growth of the mammary glands.[68][69] These effects appear to be downstream actions of increased activation of the prostaglandin EP2, EP3, and EP4 receptors, but not the EP1 receptor, in mammary gland tissue, which in turn results in the potent induction of amphiregulin expression, a critical growth factor involved in normal mammary gland development.[68][69] In addition, agonists of the epidermal growth factor receptor (EGFR), the molecular target of amphiregulin, induce COX-2 expression in mammary gland tissue, potentially resulting in a self-perpetuating cycle of growth amplification by COX-2.[68][69] This mechanism is closely related to formation, growth, and spreading of cancers with poor prognosis, and is in accordance with the fact that long-term administration of aspirin, a COX inhibitor, as well as of other COX-inhibiting nonsteroidal anti-inflammatory drugs (NSAIDs), have been found to slightly reduce the risk of breast cancer in women (it is notable here that breast growth/size and breast cancer risk are positively associated).[70] Taken together, these findings indicate that COX-2 inhibitors, such as aspirin, ibuprofen, naproxen, and celecoxib, may decrease breast cell proliferation.[68][69]

Elevated levels of HGF and, to a lesser extent, IGF-1 (by 5.4-fold and 1.8-fold, respectively), in breast stromal tissue, have been found in macromastia, a very rare condition of extremely and excessively large breast size.[71] Exposure of macromastic breast stromal tissue to non-macromastic breast epithelial tissue was found to cause increased alveolar morphogenesis and epithelial proliferation in the latter.[71] A neutralizing antibody for HGF, but not for IGF-1 or EGF, was found to attenuate the proliferation of breast epithelial tissue caused by exposure to macromastic breast stromal cells, potentially directly implicating HGF in the breast growth and enlargement seen in macromastia.[71] As such, treatment with HGF or agonists of its receptor, c-Met, or potentiators of the HGF-c-Met axis (such as dihexa)[72] might have the potential to induce macromastia-like breast growth in an exposure-dependent manner.[71]

Possible increased risk of cancer

[edit]
See also: IGF-1 receptor § Role in cancer

The risk of breast cancer in women is approximately 100-fold that of men.[73] As such, the development of female-typical breasts is associated with a dramatic increase in the risk of breast cancer.[73] Moreover, breast size and breast cancer are positively correlated,[74][75] and macromastia, a condition of excessively large breast size, is considered to be a risk factor for breast cancer.[citation needed] In accordance, it has been hypothesized that there could be a further increase in the risk of breast cancer with hormonal breast enhancement.[2]

Long-term treatment with estrogens and/or progestogens in women, specifically in the form of oral contraceptives, appears to be associated with a slightly increased risk of breast cancer.[76][77] The risk appears to be highest in younger women, notably in those who started taking oral contraceptives before 20 years of age.[78] This could be related to increased synergy of estrogens with the higher levels of GH/IGF-1 that are present with younger age.[79]

Research has suggested that the enhancement of growth factor pathways, including that of GH/IGF-1, could potentially increase the risk of various cancers, including breast cancer.[80] Increased proliferation due to increased IGF-1 activity has been suggested to possibly play a key role in the high risk of breast cancer seen in women with the BRCA1 mutation.[81] Multiple large studies have found a correlation in premenopausal women between serum IGF-1 levels in the upper quartile of the normal range and IGFBP-3 levels in the lower quartile (i.e., high circulating IGF-1 levels and low circulating IFGBP-3 levels) and the risk of developing various cancers, including breast cancer.[82][83] However, the increase in breast cancer risk has been found only to be modest (e.g., only more than twice the usual risk).[84] Subsequent studies have found the increase in risk to be even less clear, and it is notable that high-normal range IGF-1 levels have been found to correlate only with premenopausal and not with postmenopausal breast cancer incidence.[85][86] In any case, mice engineered to have lower circulating levels of IGF-1 show a lower risk of developing various cancers, including breast cancer.[87] In contrast to the case of IGF-1, the upper quintile (20%) of postmenopausal women with the highest of both circulating estrogen and androgen levels have been found to have a significantly increased risk of breast cancer (relative to lowest quintile, the risk is 2- to 3-fold higher).[86] A significant positive association with breast cancer risk has also been found with prolactin levels in postmenopausal women.[86]

In acromegaly, a condition caused and maintained by highly elevated GH/IGF-1 levels, overall, there appears to be little or no increased risk of breast cancer nor certain other cancers (e.g., prostate cancer, lung cancer) relative to that of the general population.[88][89] That said, cancer risk does appear to be consistently elevated in individuals specifically with uncontrolled disease.[90] In addition, there appears to be an increased risk of colorectal cancer and pre-malignant tubular adenomas in acromegaly.[91] In any case, individuals with acromegaly appear to show no increased risk of cancer mortality or general mortality post-treatment (i.e., after their GH/IGF-1 levels have been normalized with medical treatment), and this includes breast cancer.[27][89][92] (Larger-scale studies may be needed, however.)[89][91] In contrast to acromegaly, people with Laron syndrome, a condition characterized by insensitivity to GH and very low IGF-1 levels, have a majorly reduced, in fact almost absent, risk of developing cancer, including breast cancer.[93] There has been concern expressed about doping in athletes with GH/IGF-1 and possible increased risk of cancer, including breast cancer.[94]

See also

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References

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