IGF main cause of gyno - not estro/prog

[fred9]

found the following on this site (thnx to wazzup):
http://www.endotext.org

INTRODUCTION
This chapter will review: the ontogeny and physiology of breast development; factors that influence breast enlargement in the male; the differential diagnosis of gynecomastia ; the process of diagnostic investigation; and treatment of gynecomastia.

BREAST DEVELOPMENT

Male breast development occurs in an analogous fashion to female breast development. At puberty in the female breast, complex hormonal interplay occurs resulting in growth and maturation of the adult female breast.

In early fetal life, epithelial cells, derived from the epidermis of the area programmed to later become the areola, proliferate into ducts, which connect to the nipple at the skin's surface. The blind ends of these ducts bud to form alveolar structures in later gestation. With the decline in fetal prolactin, placental estrogen and progesterone at birth, the infantile breast regresses until puberty (15).

During thelarche, the initial clinical appearance of the breast bud, growth and division of the ducts occur, eventually giving rise to club-shaped terminal end buds, which then form alveolar buds. Approximately a dozen alveolar buds will cluster around a terminal duct, forming the type 1 lobule. Eventually, the type 1 lobule will mature into types 2 and 3 lobules, called ductules, by increasing its number of alveolar buds to as many as 50 in type 2 and 80 in type 3 lobules. The entire differentiation process takes years after the onset of puberty and, if pregnancy is not achieved, may never be completed (42).

HORMONAL REGULATION OF BREAST DEVELOPMENT

The initiation and progression of breast development involves a coordinated effort of pituitary and ovarian hormones, as well as local mediators (see Figure 1).


Figure 1. Hormones affecting growth and differentiation of breast tissue. (GH= Growth Hormone ; ER= Estrogen Receptor; PR= Progesterone Receptor; AR= Androgen Receptor)

ESTROGEN, GH AND IGF-1, PROGESTERONE, & PROLACTIN

Estrogen and progesterone act in an integrative fashion to stimulate normal adult female breast development. Estrogen, acting through its ER a receptor, promotes duct growth, while progesterone, also acting through its receptor (PR), supports alveolar development (15). This is demonstrated by experiments in ER a knockout mice which display grossly impaired ductal development, whereas the PR knockout mice possess significant ductal development, but lack alveolar differentiation (28,6).

Although estrogens and progestogens are vital to mammary growth, they are ineffective in the absence of anterior pituitary hormones (13). Thus, neither estrogen alone nor estrogen plus progesterone can sustain breast development without other mediators, such as GH and IGF-1, as confirmed by studies involving the administration of estrogen and GH to hypophysectomized and oophorectomized female rats, which resulted in breast ductal development. The GH effects on ductal growth are mediated through stimulation of IGF-1. This is demonstrated by studies of estrogen and GH administration to IGF-1 knockout rats that showed significantly decreased mammary development when compared to age-matched IGF-1- intact controls. Combined estrogen and IGF-1 treatment in these IGF-1 knockout rats restored mammary growth. (23, 40). In addition, Walden et al. demonstrated that GH-stimulated production of IGF-1 mRNA in the mammary gland itself, suggesting that IGF-1 production in the stromal compartment of the mammary gland acts locally to promote breast development (49). Furthermore, other data indicates that estrogen promotes GH secretion and increased GH levels, stimulating the production of IGF-1, which synergizes with estrogen to induce ductal development.

Like estrogen, progesterone has minimal effects in breast development without concomitant anterior pituitary hormones; again indicating that progesterone interacts closely with pituitary hormones. For example, prolonged treatment of dogs with progestogens such as depot medroxyprogesterone acetate or with proligestone caused increased GH and IGF-1 levels, suggesting that progesterone may also have an effect on GH secretion (33). In addition, clinical studies have correlated maximal cell proliferation to specific phases in the female menstrual cycle. For example, maximal proliferation occurs not during the follicular phase when estrogens reach peak levels and progesterone is low (less than 1 ng/mL [3.1nmol}), but rather, it occurs during the luteal phase when progesterone reaches levels of 10-20 ng/mL (31- 62nmol) and estrogen levels are two to three times lower than in the follicular phase (42). Furthermore, immunohistochemical studies of ER and PR showed that the highest percentage of proliferating cells, found almost exclusively in the type 1 lobules, contained the highest percentage of ER and PR positive cells (42). Similarly, there is immunocytological presence of ER, PR, and androgen receptors (AR) in gynecomastia and male breast carcinoma. ER, PR and AR expression was observed in 100% (30/30) of gynecomastia cases (41). Given these data and the fact that PR knockout mice lack alveolar development in breast tissue, it appears as if progesterone, analogous to estrogen, may increase GH secretion and act through its receptor on mammary tissue to enhance breast development, specifically alveolar differentiation (28, 18).

Prolactin is another anterior pituitary hormone integral to breast development. Prolactin is not only secreted by the pituitary gland but may be produced in normal mammary tissue epithelial cells and breast tumors. (44, 25). Prolactin stimulates epithelial cell proliferation only in the presence of estrogen and enhances lobulo-alveolar differentiation only with concomitant progesterone.

ANDROGEN AND AROMATASE

Estrogen effects on the breast may be the result of either circulating estradiol levels or locally produced estrogens. Aromatase P450 catalyzes the conversion of the C19 steroids , androstenedione, testosterone , and 16-a-hydroxyandrostenedione to estrone, estradiol-17b and estriol. As such, an overabundance of substrate or an increase in enzyme activity can increase estrogen concentrations and thus initiate the cascade to breast development in females and males. For example, in the more complete forms of androgen insensitivity syndromes in genetically male (XY) patients, excess androgen aromatizes into estrogen resulting in not only gynecomastia, but also a phenotypic female appearance. Furthermore, the biologic effects of over expression of the aromatase enzyme in female and male mice transgenic for the aromatase gene result in increased breast proliferation. In female transgenetics, over expression of aromatase promotes the induction of hyperplastic and dysplastic changes in breast tissue. Over expression of aromatase in male transgenics caused increased mammary growth and histological changes similar to gynecomastia, an increase in estrogen and progesterone receptors and an increase in downstream growth factors such as TGF-beta and bFGF (17). Interestingly, treatment with an aromatase inhibitor leads to involution of the mammalian gland phenotype (27). Thus, although androgens do not stimulate breast development directly, they may do so if they aromatize to estrogen. This occurs in cases of androgen excess or in patients with increased aromatase activity.


INCREASED AROMATASE ACTIVITY

Besides tumors, other conditions have been associated with excessive aromatization of testosterone and androgens to estrogen, which results in gynecomastia. For instance, a familial form of gynecomastia has been discovered, in which affected family members have an elevation of extragonadal aromatase activity (5). More recently, novel gain-of-function mutations in chromosome 15 have been reported to cause gynecomastia, possibly by forming cryptic promoters that lead to over expression of aromatase. (43). As stated, obesity may cause estrogen excess through increased aromatase activity in adipose tissue. Furthermore, hyperthyroidism induces gynecomastia through several mechanisms, including increased aromatase activity (42).

DISPLACEMENT OF ESTROGENS FROM SHBG

Another cause of gynecomastia from estrogen excess includes steroid displacement from sex-hormone binding globulin (SHBG). SHBG binds androgens more avidly than estrogen. Thus, any condition or drug that can displace steroids from SHBG, will more easily displace estrogen, allowing for higher circulating levels of estrogen. Drugs can cause gynecomastia by numerous mechanisms besides displacement from SHBG. These drugs and their mechanisms will be addressed in a subsequent section.

DECREASED TESTOSTERONE AND ANDROGEN RESISTANCE

Breast development requires the presence of estrogen. Androgens, on the other hand oppose the estrogenic effects. Thus, equilibrium exists between estrogen and androgens in the adult male to prevent growth of breast tissue, whereby either an increase in estrogen or a decrease in androgen can tip the balance toward gynecomastia. Increased estrogen levels will increase glandular proliferation by several mechanisms. These include direct stimulation of glandular tissue and by suppressing LH, therefore decreasing testosterone secretion by the testes and exaggerating the already high estrogen to androgen ratio.

Besides increased estrogen production, decreased testosterone levels can cause an elevation in the estrogen to androgen ratio, producing gynecomastia. Primary hypogonadism, with its reduction in serum testosterone and increased serum LH levels increases testicular estradiol production and is associated with an increased estrogen to androgen ratio. Klinefelter's syndrome, occurring in 1 in 500 males who possess an XXY karyotype and primary testicular failure, features gynecomastia as well, again presumably secondary to decreased testosterone production, compensatory increased LH secretion, overstimulation of the Leydig cells and relative estrogen excess. In addition, any acquired testicular disease resulting in primary hypogonadism such as viral and bacterial orchitis, trauma, or radiation can also promote gynecomastia by the same mechanisms (30). Lastly, enzyme deficiencies in the testosterone synthesis pathway from cholesterol also result in depressed testosterone levels and hence a relative increase in estrogen. Deficiency of 17-oxosteroid reductase, the enzyme that catalyzes the conversion of androstenedione to testosterone and estrone and estrone to estradiol, for example, will cause elevation in estrone and androstenedione, which is then further aromatized to estradiol (7).

Secondary hypogonadism, if severe enough, results in low serum testosterone and unopposed estrogen effect from increased conversion of adrenal precursors to estrogens (30). Thus, patients with Kallmann's syndrome, a form of congenital secondary hypogonadism with anosmia, also develop gynecomastia. In fact, hypogonadism from whatever cause constitutes most cases of gynecomastia.

The androgen resistance syndromes, including complete and partial testicular feminization (e.g. Reifenstein's syndrome) are characterized by gynecomastia and varying degrees of pseudohermaphroditism. Kennedy Syndrome, a neurodegenerative disease, is also associated with decreased effective testosterone due to a defective androgen receptor (42). The gynecomastia is the combined result of decreased androgen responsiveness at the breast level and increased estrogen levels as a result of elevated androgen precursors of estradiol and estrone. As such, androgens in these diseases are not recognized by the peripheral tissues including the breast and pituitary. Androgen resistance at the pituitary results in elevated serum LH levels and increased circulating testosterone. The increased serum testosterone is then aromatized peripherally, promoting gynecomastia. Thus, gynecomastia is the result of increased estradiol levels that arise due to unopposed androgen unresponsiveness.

OTHER DISEASES

Other disease states have also resulted in gynecomastia.

Men with end stage renal disease may have reduced testosterone, and elevated gonadotropins. This apparent primary testicular failure may then lead to increased breast development (18).

The gynecomastia of liver disease, particularly cirrhosis, does not have a clear etiology. Some have speculated that the gynecomastia is the result of estrogen overproduction, possibly secondary to increased extraglandular aromatization of androstenedione, which may have decreased hepatic clearance in cirrhotics. However, testosterone administration to cirrhotics causes a rise in estradiol, but decreases the prevalence of gynecomastia (13, 3, 37). Therefore, although the association of gynecomastia with liver disease is apparent, current data are conflicting and the mechanism by which this occurs remains unclear.

As previously stated, thyrotoxicosis is associated with gynecomastia. Patients often have elevated estrogen that may result from a stimulatory effect of thyroid hormone on peripheral aromatase. Testosterone may also be increased possibly due to thyroid-hormone-stimulated increase in SHBG, as free testosterone is usually normal. Since SHBG binds testosterone more avidly than estradiol, there is a higher ratio of free estradiol to free testosterone. Thus, with normal testosterone and increased estrogen, there is an elevated estrogen to testosterone ratio. In addition, LH is also increased, which may also stimulate testicular estrogen synthesis (18, 10).

Gynecomastia can also follow spinal cord disorders. Most patients with spinal cord disorders display depressed testosterone levels and, in fact, can develop testicular atrophy with resultant hypogonadism and infertility. Some have speculated that this may result from recurrent urinary tract infections, increased scrotal temperature, and a neuropathic bladder, which ultimately cause acquired primary testicular failure. The exact mechanism, however, remains elusive (19).

Refeeding gynecomastia refers to breast development in men recovering from a malnourished state (15). Although most cases regress within seven months, the etiology of this phenomenon has not been fully elucidated.

HIV patients can also develop gynecomastia. There is a high incidence of androgen deficiency due to multifactorial causes, including primary and secondary hypogonadism (30).

DRUGS

A significant percentage of gynecomastia is caused by medications or exogenous chemicals that result in increased estrogen effect. This may occur by several mechanisms: 1) they possess intrinsic estrogen-like properties, 2) they increase endogenous estrogen production, or 3) they supply an excess of an estrogen precursor (e.g. testosterone or androstenedione) which can be aromatized to estrogen. Examples of drugs that cause gynecomastia are listed in Tables 2 and 3. Contact with estrogen vaginal creams, for instance, can elevate circulating estrogen levels. These may or may not be detected by standard estrogenic qualitative assays. An estrogen-containing embalming cream has been reported to cause gynecomastia in morticians (4, 14). Recreational use of marijuana, a phytoestrogen, has also been associated with gynecomastia. It has been suggested that digitalis causes gynecomastia due to its ability to bind to estrogen receptors (18, 39). The appearance of gynecomastia has been described in body builders and athletes after the administration of aromatizable androgens. The gynecomastia was presumably caused by an excess of circulating estrogens due to the conversion of androgens to estrogen by peripheral aromatase enzymes (9).

Drugs and chemicals that cause decreased testosterone levels either by causing direct testicular damage, by blocking testosterone synthesis, or by blocking androgen action can produce gynecomastia. For instance, phenothrin, a chemical component in delousing agents, possessing antiandrogenic activity, has been attributed as the cause of an epidemic of gynaecomastia among Haitian refugees in US detention centers in 1981 and 1982 (8). Chemotherapeutic drugs, such as alkylating agents, cause Leydig cell and germ cell damage, resulting in primary hypogonadism. Flutamide, an anti-androgen used as treatment for prostate cancer, blocks androgen action in peripheral tissues, while cimetidine blocks androgen receptors. Ketoconazole, on the other hand, can inhibit steroidogenic enzymes required for testosterone synthesis. Spironolactone causes gynecomastia by several mechanisms. Like ketoconazole, it can block androgen production by inhibiting enzymes in the testosterone synthetic pathway (i.e. 17a hydroxylase and 17-20-desmolase), but it can also block receptor-binding of testosterone and dihydrotestosterone (45). In addition to decreasing testosterone levels and biologic effects, spironolactone also displaces estradiol from SHBG, increasing free estrogen levels. Ethanol increases the estrogen to androgen ratio and induces gynecomastia by multiple mechanisms as well. Firstly, it is associated with increased SHBG, which decreases free testosterone levels. Secondly, it increases hepatic clearance of testosterone, and thirdly, it has a direct toxic effect on the testes themselves (30). Unfortunately, besides the drugs stated, a multitude of others cause gynecomastia by unknown mechanisms (Table 3).

Table 2. Drugs that induce gynecomastia by known mechanisms
Estrogen-
like, or binds to estrogen receptor Stimulate estrogen synthesis Supply aromatizable estrogen precursors Direct Testicular Damage Block testosterone synthesis Block androgen action Displace estrogen from SHBG
Estrogen vaginal cream Gonado-
tropins Exogenous androgen Busulfan Ketoconazole Flutamide Spironol-
actone
Estrogen-
containing embalming cream Growth Hormone Androgen precursors (ie androstene-
dione and DHEA) Nitrosurea Spironol-
actone Bicalut-
amide Ethanol
Delousing powder Vincristine Metronidazole Finasteride
Digitalis Ethanol Etomidate Cyproterone
Clomiphene Zanoterone
Marijuana Cimetidine
Ranitidine
Spironol-
actone



Table 3. Drugs that cause gynecomastia by uncertain mechanisms:
Cardiac and antihypertensive medications:
Calcium channel blockers (verapamil, nifedipine, diltiazem)
ACE Inhibitors (captopril, enalapril
b blockers
Amiodarone
Methyldopa
Reserpine
Nitrates

Psychoactive drugs:
Neuroleptics
Diazepam
Neuroleptics
Diazepam
Phenytoin
Tricyclic antidepressants
Haloperidol


Drugs for infectious diseases:
Indinavir
Isoniazid
Ethionamide
Griseofulvin

Drugs of Abuse:
amphetamines

Other:
Theophylline
Omeprazole
Auranofin
Diethylpropion
Domperidone
Penicillamine
Sulindac
Heparin

TREATMENT

Treatment of the underlying endocrinologic or systemic disease that has caused gynecomastia is mandatory. Testicular tumors, such as Leydig cell, Sertoli cell or granulosa cell tumors should be surgically removed. In addition to surgery, germ cell tumors are further managed with chemotherapy involving cisplatin, bleomycin and either vinblastine or etoposide (38, 16). Should underlying thyrotoxicosis, renal or hepatic failure be discovered, appropriate therapy should be initiated. Medications that cause gynecomastia should also be discontinued whenever possible based on their role in management of the underlying condition. Of course, if a breast biopsy indicates malignancy, then mastectomy should be performed.

If no pathologic abnormality is detected, then appropriate treatment is close observation. A careful breast exam should be done initially every 3 months until the gynecomastia regresses or stabilizes, after which a breast exam can be performed yearly. It is important to remember that some cases of gynecomastia, especially that which occurs in pubertal boys, can resolve spontaneously.

MEDICAL TREATMENT

If the gynecomastia is severe, does not resolve, and does not have a treatable underlying cause, some medical therapies may be attempted. There are 3 classes of medical treatment for gynecomastia: androgens (testosterone, dihydrotestosterone, danazol), anti-estrogens (clomiphene citrate, tamoxifen ) and aromatase inhibitors such as testolactone. Testosterone treatment of hypogonadal men with gynecomastia often fails to produce breast regression once gynecomastia is established. Unfortunately, testosterone treatment may actually produce the side effect of gynecomastia by being aromatized to estradiol. Thus, although testosterone is used to treat hypogonadism, its use to specifically counteract gynecomastia is limited (47). Dihydrotestosterone, a non-aromatizable androgen, has been used in patients with prolonged pubertal gynecomastia with good response rates (24). Since dihydrotestosterone is given either intramuscularly or percutaneously, this may restrict its usefulness. Danazol, a weak androgen that inhibits gonadotropin secretion, resulting in decreased serum testosterone levels, has been studied in a prospective placebo-controlled trial, whereby gynecomastia resolved in 23 percent of the patients, as opposed to 12 percent of the patients on placebo (22). Unfortunately, undesirable side effects including edema, acne, and cramps have limited its use (30). Investigators have reported a 64 percent response rate with 100 mg/day of clomiphene citrate, a weak estrogen and moderate antiestrogen (26). Lower doses of clomiphene have shown varied results, indicating that higher doses may need to be administered, if clomiphene is to be attempted. Tamoxifen, also an antiestrogen, has been studied in 2 randomized, double-blind studies in which a statistically significant regression in breast size was achieved, although complete regression was not documented (1). One study compared tamoxifen with danazol in the treatment of gynecomastia. Although patients taking tamoxifen had a greater response with complete resolution in 78 percent of patients treated with tamoxifen, as compared to only a 40 percent response in the danazol-treated group, the relapse rate was higher for the tamoxifen group (46). Although complete breast regression may not be achieved and a chance of recurrence exists with therapy, tamoxifen, due to relatively lower side effect profile, may be a more reasonable choice when compared to the other therapies. If used, tamoxifen should be given at a dose of 10 mg twice a day for at least 3 months (30). An aromatase inhibitor, testolactone, has also been studied in an uncontrolled trial with promising effects (51). Further studies must be performed on this drug before any recommendations can be established on its usefulness in the treatment of gynecomastia. Newer aromatase inhibitors such as anastrozole and letrozole may have therapeutic potential but no study has been published to confirm its efficacy in treatment of gynecomastia. (32)

SURGICAL TREATMENT

When medical therapy is ineffective, particularly in cases of longstanding gynecomastia, or when the gynecomastia interferes with the patient's activities of daily living, or when there is suspicion of malignancy of breast, then surgical therapy is appropriate. This includes removal of glandular tissue coupled with liposuction, if needed. In our experience, uses of delicate cosmetic surgical techniques are warranted to prevent unsightly scarring.

PREVENTION OF GYNECOMASTIA IN MEN WITH PROSTATE CANCER

Because androgen deprivation is one of the commonly used treatment modalities for advanced prostate cancer, its possible role in the development of gynecomastia is of particular concern to clinicians. Low dose prophylactic irradiation has been variably reported to reduce the rate of gynecomastia in men receiving estrogens or antiandrogens for advanced prostate cancer (11) (48).

SUMMARY

In summary, gynecomastia is a relatively common disorder. The causes of its development range vastly from benign physiologic processes to rare neoplasms. Thus, in order to properly diagnose the etiology of the gynecomastia, the clinician must understand the hormonal factors involved in breast development. Parallel to female breast development, estrogen, along with GH and IGF-1 is required for breast growth in males. Since a balance exists between estrogen and androgens in males, any disease state or medication that can increase circulating estrogen or decrease circulating androgen, causing an elevation in the estrogen to androgen ratio, can induce gynecomastia. Due to the diversity of possibly etiologies, including neoplasm, performing a careful history and physical is imperative. Once gynecomastia has been diagnosed, treatment of the underlying cause is warranted. If no underlying cause is discovered, then close observation is appropriate. If the gynecomastia is severe, however, medical therapy can be attempted and if ineffective, glandular tissue can be removed surgically

[goose]

Once again dude,thanks for the great information......

[vermin]

IGF main cause of gyno - not estro/prog

I don't think that is what this says - it merely points out that IGF is a necessary mediator for estrogen and progesterone to have their effects. Interesting perhaps in an academic way, but really not very relevant to us here. After all, IGF is necessary for much that happens in physiology particularly as relates to growth of new tissues, which is what we are mostly seeking.

So, IGF good, estrogen in correct amounts good (also required for muscle growth, cholesterol control, etc.), estrogen too high bad. Same as it ever was.

[ss01]

In the past, when it was legal of course, I used GHB & sugar as a cheap GH & Slin == IGF-1 stack. I did not know that GHB also increased prolactin too. Guess what? Gyno.

[fred9]

I don't think that is what this says - it merely points out that IGF is a necessary mediator for estrogen and progesterone to have their effects. Interesting perhaps in an academic way, but really not very relevant to us here. After all, IGF is necessary for much that happens in physiology particularly as relates to growth of new tissues, which is what we are mostly seeking.

So, IGF good, estrogen in correct amounts good (also required for muscle growth, cholesterol control, etc.), estrogen too high bad. Same as it ever was.

they mentioned that gyno can only be created if there's igf around, thus there should be no gyno with high levels of estro+prog without igf...So in this point of view a dopamine-agonist like bromocriptine or dostinex should be enough to stop gyno...also the prolactin lactation problem is solved with dop-agonist

[alllooksnnogo]

Very good ifo dude. Thanks for sharing it with us.

Ok, here is my situation

details:

Completed my last AS cycle in April and ran IGFR3 for the first time. I ran this for my PCT and finished in May. I liked it alot. Not alot of gain but I kept alot of muscle and my BF decreased.

I had good results off of the IGF but soon I will take IGF for the first time with a cycle. Tren /test prop will be my main focus this time and I read that Tren increases IGF sensitivity. Great right!! Sounds good, however, I am pron to progestrogenic gyno.....Deca did me in a few cycles ago. I got lucky as I stopped the deca and the pain/most of the gyno subsided. Now nolvy and clomid did nothing to help my situation. As I researched more I found that if I had used a DHT compund such as proviron or winny thus not only blocking the receptor but taking it I would have been ok.

blah blah...now upon reading this information I am worried that with the increase in IGF and the AS together I might be again pron to gyno.

What do you experienced bros think. If I run proviron thru the cycle, which was the plan anyway, and am also running 6 weeks of winny at the end. Do you think that this will be enough to hold back any gyno?

I have no problems with any compounds like test that have a higher affinity to aromatize into estrogen. I also usually run nolvy straight thru as well just in case, but I've never had trouble in the past even running 750mg test/ week without.

Thanks in advance

Matt

[vermin]

they mentioned that gyno can only be created if there's igf around, thus there should be no gyno with high levels of estro+prog without igf...So in this point of view a dopamine-agonist like bromocriptine or dostinex should be enough to stop gyno...also the prolactin lactation problem is solved with dop-agonist

That is not what you titled the thread however, you stated that IGF is the cause for gyno, and now we get folks thinking that their IGF cycles are gonna cause gyno....

[G-1000]

^^^^^^^^

[fred9]

That is not what you titled the thread however, you stated that IGF is the cause for gyno, and now we get folks thinking that their IGF cycles are gonna cause gyno....

sorry for late response, just back from vacation...

the title is wrong, just like you said...
what i meant: that igf is the crucial factor in breast development, when you look at the whole interaction between all the hormones that play a part of it..

ill place later on a better post...now a little bit to tired:S