The Use of Testosterone Replacement in Women - Is it Worth it and Safe?

By Nelson Vergel

Author of "Testosterone: A Man's Guide"

There is so much confusion about the use of hormones in pre and post menopausal women, especially after the largest study ever undertaken using two female hormones was halted due to increased incidence of breast cancer in women.  I will try to attempt to distill issues related not only to female based hormone therapy (estrogen and progestin) but also to the use of testosterone replacement therapy in women.


WHAT IS TESTOSTERONE? ISN'T IT A MALE HORMONE?

Testosterone is the hormone responsible for normal growth and development and maintenance of male sex characteristics.  It also affects lean body mass, mood and sexual function in both males and females, so it is not only a "male" hormone. It is the primary androgenic (responsible for masculine characteristics) and anabolic (muscle building) hormone.

Testosterone is produced by the testicles in males and by the ovaries in females, with small amounts also produced by the adrenal glands in both genders. Men produce about 7-8 times more testosterone than women.

Testosterone is also the precursor of estradiol (a "female" hormone) in men and women.

SEXUAL DYSFUNCTION IN WOMEN

As we all know if we watch TV for more than an hour, we are bombarded daily by ads selling erectile dysfunction drugs for men.  But we hardly hear anything about sexual dysfunction in women, and there are many reasons why women’s sexual desire and other hormone related quality of life issues are so misunderstood, under-diagnosed and under treated.

There is no FDA approved product for the treatment of sexual dysfunction in women. There is also no FDA approved testosterone replacement product for women in 2012, although  some physicians are prescribing it to women in an "off-label" manner (legal but not for the FDA approved "intended use") using  low doses of  commercial products approved for men (Androgel, Testim, Fortesta, Testopel, Depo Testosterone and Axiron) or via compounded pharmacy  gel/cream formulations.

Sexual dysfunction in pre and post-menopausal women has been a very controversial topic that has been poorly researched even though a February, 1999 study published in the Journal of the American Medical Association, titled, “Sexual Dysfunction in the United States: Prevalence and Predictors,” found that approximately 43% of postmenopausal women suffer from some form of female sexual dysfunction.

It wasn’t until June 2011 that an FDA advisory committee to the division of Reproductive and Urologic Drug Products stated that HSDD (Hypoactive Sexual Desire Syndrome) is a significant medical condition for women. This may open the door for companies to apply for new drug applications for that indication.

It is important to note that unlike erectile dysfunction drugs approved for men like Viagra that increase blood flow to the genitals as long as a man is aroused,  testosterone therapy is systemic and needs to be applied over a period of weeks  to have a noticeable effect on sex drive in men and women.

 Some companies have tried to enter the female sexual dysfunction market in the past. In December 2004 the United States theFDA rejected Procter and Gamble's   fast-track request for Intrinsa (a testosterone patch for women) for  HSDD citing concerns about potential off-label use of the product was to be approved. In Canada, post-menopausal women have been able to obtain government-approved testosterone treatment since 2002.  In 2007, Intrinsa was granted a license from the European Medicines Agency in July, and is available on Britain's National Health Service.

 According to a P&G's survey on female health, 30 million women in the U.S. are naturally menopausal, 3 million are distressed by their lack of sexual desire, and 20% of 25 million women who are surgically menopausal are distressed.

Other companies that attempted to get their drugs approved for this indication (Boehringer Ingelheim and Warner Chilcott) have each pulled the plug on their competing HSDD treatments for menopausal and pre-menopausal women.

BioSante Pharmaceuticals is the only company left in the race for a treatment for HSDD.  This company is in late stage clinical studies using LibiGel (testosterone gel) treatment of HSDD but has had issues in the approval of this product by the FDA.  More on this product at the end of this article.

HORMONE THERAPY IN POST MENOUPAUSAL WOMEN

Menopause can cause symptoms such as hot flashes might result from the changing hormone levels during the menopause transition. After a woman's last menstrual period, when her ovaries make much less estrogen and progesterone, some symptoms of menopause might disappear, but others may continue.

To help relieve these symptoms, some women use hormones. This is called hormone therapy (HT) which includes estrogen alone or in combination with progestin.  HT is available orally or in gel formulations made by specialized compounding pharmacies.

Estrogen is a hormone used to relieve the symptoms of menopause. Estrogen alone (E) may be used by a woman whose uterus has been removed.  But a woman who still has a uterus must add progesterone or a progestin (synthetic progesterone) along with the estrogen (E+P). This combination lowers the chance of an unwanted thickening of the lining of the uterus and reduces the risk of cancer of the uterus, an uncommon, but possible result of using estrogen alone.

But the use of hormone therapy in women has been subject of a lot on controversy in  recent past.

Researchers from the Harvard School of Public Health analyzed data from the landmark Women's Health Initiative (WHI) clinical trial of the effects of combination hormone therapy  (estrogen+ progestin) in 16,608 postmenopausal women with an intact uterus, ages 50 to 79 years (average age of 63) at enrollment. This study did not include the use of testosterone. In this study,  8,506 participants were randomly assigned to receive a combination of estrogen (0.625 milligrams of conjugated equine estrogens per day) plus progestin (2.5 mg of medroxyprogesterone acetate), and 8,102 women were given placebo. 

The study was stopped in 2002 after an average of 5.6 years of treatment due to an increase in breast cancer in the women on hormone therapy. Compared to women on placebo, women on combination hormone therapy were also at increased risk of stroke, dangerous blood clots, and heart disease, while their risk of colorectal cancer and hip fractures was lower.

 It is important to note that these hormones were provided orally and that some clinicians claim that transdermal (on the skin) application  of estrogen alone or in combination with testosterone would show a different and more favorable side effect profile.

 The halting of the WHI study raised concerns about safety of all hormone therapy in women (oral or transdermal), even if no androgens will included in this study and only oral delivery forms were used.  Many physicians stopped prescribing hormone therapy (HT) even for women who had dramatic improvements in their quality of life while using it.  Experts today don't recommend hormone therapy unless a woman suffers difficult menopause symptoms.

Emerging data on the use of androgens (testosterone and DHEA) alone or in combination with HT are showing that there may be potential benefits of these hormones in women with androgen deficiency and sexual dysfunction.

Androgens are also precursors of all estrogens (estrone (E1), estradiol (E2), and estriol (E3)) in women's bodies. The primary and most well-known androgen is testosterone (which aromatizes into estradiol), other less important androgens are dihydrotestosterone (DHEA) and androstenedione. Androgens are directly secreted by the ovaries and adrenals in women.

Presently, there is no agreement about whether androgen deficiency is a clinical problem in aging women and if the addition of androgens to HT can ameliorate the cardiovascular risks seen in the WHI study.

Causes of androgen insufficiency in women can have ovarian, adrenal, hypothalamic-pituitary, drug-related, and unknown origins. Symptoms of androgen insufficiency in women may include a diminished sense of well-being, low mood, fatigue, and hypoactive sexual desire disorder  (HSDD) with decreased libido, or decreased sexual receptivity and pleasure that causes a great deal of personal distress.

There is increasing evidence to suggest that many postmenopausal women experience symptoms alleviated by androgen therapy and that such symptoms may be caused by androgen deficiency. Affected women complain of fatigue, low libido, and diminished well-being, which are symptoms easily and frequently attributed to psychosocial and environmental factors.

The question of whether adding testosterone therapy to conventional postmenopausal HT is effective or safe is unresolved. Therefore, a Cochrane review was performed to determine the efficacy and safety of testosterone therapy for postmenopausal women using HT. Thirty-five trials with a total of 4768 participants were included in the review. The median study duration was six months (range 1.5 to 24 months). Most of the trials were of adequate quality with regard to randomization. The pooled estimate suggested that the addition of testosterone to HT regimens improved sexual function scores and number of satisfying sexual episodes for postmenopausal women. Some of the few adverse effects were decreased high-density lipoprotein (HDL) cholesterol levels and an increased incidence of hair growth and acne. The discontinuation rate was not significantly greater with the addition of testosterone therapy.

OTHER USES IN WOMEN

Emerging and controversial potential indications for androgen therapy in women have been or are being evaluated. These include use in women with premature ovarian failure, premenopausal androgen deficiency symptoms, postmenopausal and glucocorticosteroid-related bone loss, treatment of HIV related wasting, and management of premenstrual syndrome. Whether or not any of these indications will actually have approved products in the future is unknown.

HYPOGONADISM IN MEN, BUT WHAT TO CALL IT IN WOMEN?

The term hypogonadism  is used as a diagnosis term for testosterone deficiency in men.  Besides HSDD as one of the potential symptoms, there is no agreement on what to call androgen deficiency  in women.   In clinical guidelines published in 2002 called the Princeton consensus statement (Fertil Steril. 2002 Apr;77(4):660-5)  used the term "female androgen insufficiency"  as  defined  as by  a pattern of clinical symptoms in the presence of decreased bioavailable testosterone and normal estrogen status . 

The panel warned that currently available testosterone assays were found to be lacking in sensitivity and reliability at the lower testosterone blood level ranges present in women, and the need for an equilibrium dialysis measure was strongly emphasized as the most adequate method to test women’s testosterone blood levels.

TESTOSTERONE REPLACEMENT IN WOMEN- POTENTIAL BENEFITS

Circulating testosterone in women declines during the late reproductive years such that otherwise healthy women in their 40s have approximately half the testosterone level as women in their 20s. The levels remain stable across the menopausal transition and then either remain stable or continue to decline with diminishing adrenal androgen production with increasing age.  In the decade preceding menopause, there is loss of the mid-cycle surge of free testosterone.  Despite this, research showing the benefits of androgen replacement has been limited to the postmenopausal years.

Some small studies have been done in premenopausal women, however. One evaluated the efficacy of transdermal testosterone therapy on mood, well-being, and sexual function in eugonadal (normal testosterone blood levels), premenopausal women presenting with low libido. Testosterone therapy improved well-being, mood, and sexual function in these women. Since a substantial number of women experience diminished sexual interest and well-being during their late reproductive years, further research is warranted to evaluate the benefits and safety of longer-term intervention. Potential side effects that are dose dependent may be unwanted hair growth, masculinization, and lowering of high density lipoprotein (HDL).

TESTOSTERONE IN HIV+ WOMEN:

Dr Bhasin and his team (JCEM 83 (4): 1312) has found that the higher the HIV viral load, the lower the blood levels of testosterone in HIV+ women. In general, HIV+ women had lower testosterone than HIV- women. Low testosterone was not correlated to unintentional weight loss in Bhasin's data.

In healthy women, the ovaries and the adrenal glands contribute equally to the maintenance of circulating testosterone levels. Bhasin presumes that there may be some HIV effect on the ovaries that may be one of the root causes of testosterone deficiency in women with HIV.

In HIV+ women with unintentional weight loss, a placebo controlled study using testosterone a testosterone patch did not improve lean mass and strength, although Bhasin mentions that the study was not powered to determine if women with low serum free testosterone at baseline had different gains that those who had normal testosterone (the study allowed any baseline testosterone blood level as long as there had been a weight loss of 5% or more at baseline).

A study done by Dr Grinspoon’s team (Arch Intern Med. 2004 Apr 26;164(8):897-904.) showed that low dose testosterone supplementation in HIV+ women with unintentional weight loss increased lean body mass and strength. The study did not specify how many of these women had low testosterone at baseline, however.

Presented in CROI-2009 (Abstract 976), a 18 month randomized placebo-controlled study performed by Dr. Labby and colleagues from Harvard Medical School investigated the effects of transdermal (patch) testosterone replacement (300 mcg twice weekly vs. placebo) on body composition, bone density, metabolic parameters, quality of life, and safety among relatively androgen deficient women with HIV. 

Significantly benefits were seen with the use of testosterone replacement in  body composition, quality of life and bone density in HIV positive women who had baseline free testosterone levels below 3 picograms per milliliter (pg/mL) (the normal range is between 1.1 and 6.3 pg/m). Testosterone use was well tolerated without virilizing effects and did not affect lipids, liver function, or HIV viral load.

Most HIV+ women that I talk to have never had their testosterone blood levels checked. Unfortunately, most  HIV clinical practices in the United States have not recognized androgen deficiency diagnosis and treatment even in well insured women with symptoms of low sex drive, fatigue, loss of lean body mass, and menstrual irregularities. 

TESTOSTERONE IN HIV+ WOMEN WITH LIPODYSTROPHY

Dr Grispoon and his team have surprisingly found that free serum testosterone was three times higher in women with lipodystrophy compared to those without lipodystrophy and healthy controls (J Clin Endocrinol Metab. 2000 Oct;85(10):3544-50). In the past 15 years lecturing on metabolic disorders in HIV around the country, I have  met dozens of  HIV+ women that have been on antiretrovirals for years who have some signs of masculinization (facial hair growth and wider jaw line).  Some had been diagnosed with Polycystic Ovary Syndrome (PCOS) but others had never been examined for this diagnosis.

Women with Polycystic Ovary Syndrome (PCOS) have higher levels of testosterone and insulin in general.  The main symptoms of PCOS are menstrual irregularities, hirsutism, acne, infertility metabolic syndrome, and others.  Metformin, an insulin sensitizer, and finasteride, a dehydrotestosterone (DHT) inhibitor, have been shown to normalize testosterone in women with PCOS.

Dr Grispoon and his team found that HIV+ women with severe lipodystrophy had no higher incidence of PCOS, but some other reports contradict this finding (JCEM 90 (10): 5596).

So, is higher testosterone in HIV+ women with lipodystrophy caused by HIV, inflammatory factors, or multifactorial?  I do not think we will ever find out, but I think it is prudent to measure total and free testosterone in HIV+ women with lipodystrophy that may be experiencing menstrual problems and/or excessive hair growth. 

TESTOSTERONE REPLACEMENT AND CARDIOVASCULAR RISKS IN WOMEN

A direct association between testosterone and heart disease has never been established, but for many years, doctors have suspected that a link exists. The reasoning goes like this: men have much more testosterone than women, and they develop heart disease about 10 years before their female counterparts.

Women with systolic heart failure who took low-dose testosterone for six months, on top of standard medical therapy, showed significant gains in exercise and ventilatory capacity and large-muscle strength along with heightened insulin sensitivity, in a small placebo-controlled trial ( J Am Coll Cardiol 2010; 56:1310-1316).

Despite the entrenched belief that higher blood levels of testosterone increase the risk of CVD in women, data from recent observational studies mostly show an inverse relationship between testosterone and CVD risk.  A pilot study (JCEM 86 (1): 158) suggested favorable effects of transdermal testosterone treatment of women with established congestive cardiac failure which merits further evaluation. Preliminary data indicate that injectable testosterone therapy improves both endothelial-dependent (flow-mediated) and endothelium-independent (GTN-mediated) brachial artery vasodilation in postmenopausal women using long-term estrogen therapy. The mechanisms underlying these potentially beneficial cardiovascular effects require further investigation.

  

TESTOSTERONE REPLACEMENT AND CANCER IN WOMEN

The relationship between endogenous testosterone production and breast cancer risk remains contentious, with recent studies indicating either no relationship, or a possible increase in risk when estrone and estradiol are not taken into account. No randomized controlled trial of testosterone therapy has been sufficiently large or of sufficient duration to establish whether such treatment may influence breast cancer occurrence. There does not appear to be an association between testosterone and endometrial cancer, or other malignancies on review of published studies.

There is now convincing evidence that usual estrogen based hormone therapy for ovarian failure increases the risk for breast cancer. However, some studies have previously shown that ovarian androgens normally protect mammary epithelial cells from excessive estrogenic stimulation, and therefore a study hypothesized that the addition of testosterone to usual hormone therapy might protect women from breast cancer (Menopause: Sept/Oct 2004 - Volume 11 - Issue 5 - pp 531-535). This was a retrospective, observational study that followed 508 postmenopausal women receiving testosterone in addition to usual hormone therapy in South Australia. Breast cancer status was ascertained by mammography at the initiation of testosterone treatment and biannually thereafter. The average age at the start of follow-up was 56.4 years, and the mean duration of follow-up was 5.8 years. Breast cancer incidence in this group was compared with that of untreated women and women using usual hormone therapy reported in the medical literature and to age-specific local population rates.

There were seven cases of invasive breast cancer in this population of testosterone users, for an incidence of 238 per 100,000 woman-years. The rate for estrogen/progestin and testosterone users was 293 per 100,000 woman-years-substantially less than women receiving estrogen/pro-gestin in the Women's Health Initiative study (380 per 100,000 woman-years) or in the Million Women Study (521 per 100,000 woman-years). The breast cancer rate in  testosterone users in this study was closest to that reported for users who never used hormone therapy  in the latter study (283 per 100,000 woman-years), and their age-standardized rate was the same as for the general population in South Australia.

These observations suggest that the addition of testosterone to conventional hormone therapy for postmenopausal women does not increase and may indeed reduce the hormone therapy-associated breast cancer risk-thereby returning the incidence to the normal rates observed in the general, untreated population. But more studies are needed.

CURRENT USE IN THE UNITED STATES

As previously mentioned, there is not a FDA approved testosterone product for women.  The few physicians that are prescribing it are doing so by having their female patients use low doses of products approved for male hypogonadism  (Androgel ,Testim, Axiron, Testopel and Fortesta) in an off label manner, or prescribing gels with small testosterone concentrations via compounding pharmacies. 

LIBIGEL, THE FIRST GEL THAT COULD HAVE BEEN APPROVED IN THE UNITED STATES FOR WOMEN

On January 24, 2008, the US FDA notified BioSante that it had completed and reached agreement with BioSante on a Special Protocol Assessment (SPA) for BioSante's Phase III safety and efficacy clinical trials of LibiGel in the treatment  of hypoactive sexual desire syndrome (HSDD).

Both Phase III safety and efficacy trials were finished and were double-blind, placebo-controlled trials that have enrolled approximately 500 surgically menopausal women each for six-months of treatment.

Unfortunately, BioSante Pharmaceuticals reported in December of 2011 that LibiGel did not meet the co-primary or secondary endpoints in two pivotal Phase III efficacy trials in the treatment of hypoactive sexual desire disorder in postmenopausal women, so the FDA did not approve it.

The co-primary endpoints of both LibiGel efficacy trials were the change in the total number of days with a satisfying sexual event from baseline, and the change in mean sexual desire from baseline. The secondary endpoint for both trials was the change in sexual distress from baseline.

Women in the first trial, called BLOOM-1, who were treated with LibiGel showed an increase of 1.47 days with a satisfying sexual event compared to baseline, while those receiving placebo gel showed an increase of 1.26 days with a satisfying sexual event compared to baseline.

Women in BLOOM-2 who were treated with LibiGel showed an increase of 1.0 day with a satisfying sexual event compared to baseline, while those receiving placebo gel showed an increase of 1.28 days with a satisfying sexual event compared to baseline.

Although there were no statistical differences in the endpoints, BioSante said all results were in the appropriate directions. The LibiGel groups in both trials showed an increase in free testosterone levels compared to baseline and placebo.

BioSante continues to conduct the Phase III LibiGel safety study, a cardiovascular events and breast cancer study that has completed enrollment of 3,656 women and has accrued over 5,100 women-years of exposure, to date. The study is designed for a total of five years; however, BioSante could use the safety study data as part of a New Drug Application (NDA) submission after the last subject enrolled has completed 12 months of exposure to LibiGel or placebo.

CONCLUSION

In conclusion, testosterone replacement in androgen deficient women with or without HIV may have a good risk-to-benefit ratio for some patients, but conflicting data, lack of long term studies and lack of a FDA approved product for that indication may be barriers to making it part of standard of care of aging women.   The approval of a testosterone product specifically for women in the future may change that.

More studies need to be performed with validated and meaningful endpoints. In the meanwhile, many women are not waiting for long term studies and instead are getting off-label prescriptions of compounded testosterone from physicians who specialize in female hormone balance. 


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Nelson Vergel is the author of "Testosterone: A Man's Guide" and co-author of the book "Built to Survive", the founder of the Body Positive Wellness Clinic in Houston, and an expert speaker on exercise, nutrition, testosterone replacement, metabolism , sexual function, body changes, lean body mass gain and fat loss. Aided by his chemical engineering degree and obsession for scientific data, he adds his own personal experience as he demystifies all testosterone and health myths. He has been involved in several clinical studies of supplements, hormones and exercise through his association with the National Institute of Health and private investigators. Via over 500 lectures, he has provided patient-friendly information accessible to all, independently of their knowledge base.For the last 20 years, his trial-and-error experience to improve his quality of life has paved the way for others to learn from his knowledge.

Book Web site: TestosteroneWisdom.com and Blog: testosteronewisdom.blogspot.com
Facebook page: Testosterone Replacement Discussion

Depressive Symptoms and Suicidal Thoughts Among Former Users of Finasteride (Propecia, Proscar) With Persistent Sexual Side Effects

Michael S. Irwig, MD

J Clin Psychiatry

10.4088/JCP.12m07887

Copyright 2012 Physicians Postgraduate Press, Inc.

Objective: Finasteride, a commonly prescribed medication for male pattern hair loss, has recently been associated with persistent sexual side effects. In addition, depression has recently been added to the product labeling of Propecia (finasteride 1 mg). Finasteride reduces the levels of several neuroactive steroids linked to sexual function and depression. This study assesses depressive symptoms and suicidal thoughts in former users of finasteride who developed persistent sexual side effects despite the discontinuation of finasteride.

Method: In 2010–2011, former users of finasteride (n = 61) with persistent sexual side effects for ≥ 3 months were administered standardized interviews that gathered demographic information, medical and psychiatric histories, and information on medication use, sexual function, and alcohol consumption. All former users were otherwise healthy men with no baseline sexual dysfunction, chronic medical conditions, current or past psychiatric conditions, or use of oral prescription medications before or during finasteride use. A control group of men (n = 29), recruited from the community, had male pattern hair loss but had never used finasteride and denied any history of psychiatric conditions or use of psychiatric medications. The primary outcomes were the prevalence of depressive symptoms and the prevalence of suicidal thoughts as determined by the Beck Depression Inventory II (BDI-II); all subjects self-administered this questionnaire at the time of the interview or up to 10 months later.

Results: Rates of depressive symptoms (BDI-II score ≥ 14) were significantly higher in the former finasteride users (75%; 46/61) as compared to the controls (10%; 3/29) (P < .0001). Moderate or severe depressive symptoms (BDI-II score ≥ 20) were present in 64% (39/61) of the finasteride group and 0% of the controls. Suicidal thoughts were present in 44% (27/61) of the former finasteride users and in 3% (1/29) of the controls (P < .0001).

Conclusions: Clinicians and potential users of finasteride should be aware of the potential risk of depressive symptoms and suicidal thoughts. The preliminary findings of this study warrant further research with controlled studies.

J Clin Psychiatry

Source: http://article.psychiatrist.com/dao_1-login.asp?ID=10007988&RSID=31923221437757

Study Looked at What Happens When Long Term Growth Hormone Replacement Therapy is Stopped

Discontinuing Long-Term GH Replacement Therapy—A Randomized, Placebo-Controlled Crossover Trial in Adult GH Deficiency

1. Helena Filipsson Nyström, 
2. Edna J. L. Barbosa, 
3. Anna G. Nilsson, 
4. Lise-Lott Norrman,
5. Oskar Ragnarsson and 
6. Gudmundur Johannsson

-Author Affiliations

1. Department of Endocrinology, Sahlgrenska University Hospital, and Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, SE-41345 Göteborg, Sweden

1. 
   

Abstract

Context: Adult GH deficiency (GHD) is associated with impaired quality of life (QoL) and increased cardiovascular risk. Continued long-term efficacy in terms of QoL and cardiovascular risk factors has been indicated in open surveillance studies.

Objectives: The aim was to study the impact of discontinuation of long-term GH replacement on QoL, body composition, and metabolism.

Design and Setting: We conducted a randomized, double-blind, placebo-controlled 4-month crossover trial in a referral center.

Patients: Sixty adult hypopituitary patients with GHD and more than 3 yr of continuous GH replacement therapy (mean treatment duration, 10 yr) participated in the study.

Intervention: Patients received GH or placebo.

Main Outcome Measurements: We measured QoL using validated questionnaires; body composition using computer tomography, dual-energy x-ray absorptiometry, and bioelectrical impedance spectroscopy; and insulin sensitivity using the short insulin tolerance test.

Results: Mean serum IGF-I decreased from 168± 52 to 98± 47 µg/liter during the placebo period (P< 0.001). Two QoL domains (emotional reactions and positive well-being) in the Nottingham Health Profile and Psychological General Well-Being questionnaires deteriorated during placebo, compared with GH treatment (P< 0.05). Waist circumference and sc and visceral fat mass increased, and extracellular water and muscle area decreased during the placebo period (all P< 0.05). C-reactive protein and total-, low-density lipoprotein-, and high-density lipoprotein-cholesterol increased, and insulin sensitivity improved during placebo, compared to GH treatment (P< 0.05).

Conclusion: After more than 3 yr of GH replacement therapy, a 4-month period of placebo treatment caused self-perceived deterioration in QoL and increased abdominal fat accumulation. Moreover, markers of systemic inflammation and lipid status deteriorated, whereas insulin sensitivity improved. Long-term continuous GH replacement is needed to maintain therapeutic effects of GH on QoL and cardiovascular risk factors.

HCG Use in Men

Human Chorionic Gonadotropin

Excerpt from the book “Testosterone: A Man’s Guide” by Nelson Vergel (available on Amazon.com or in different formats on TestosteroneWisdom.com). NelsonVergel@gmail.com

Human chorionic gonadotropin (HCG) (not to be confused with human growth hormone, or HGH) is a glycoprotein hormone that mimics LH (luteinizing hormone), produced in pregnancy by the developing embryo soon after conception, and later by part of the placenta. Its role is to prevent the disintegration of the corpus luteum of the ovary and to maintain the progesterone production critical for pregnancy in women. It supports the normal development of an egg in a woman’s ovary, and stimulates the release of the egg during ovulation. HCG is used to cause ovulation and to treat infertility in women.

HCG is also used in young boys when their testicles have not dropped down into the scrotum normally.  Additionally, HCG is used to increase testicular size after long-term testosterone or anabolic steroid use. However, the latter is an off-label use.

Testosterone replacement therapy triggers the hypothalamus to shut down its production of GnRH (gonadotropin releasing hormone). Without GnRH, the pituitary gland stops releasing LH. Without LH the testes (testicles or gonads) shut down their production of testosterone. For males HCG closely resembles LH. If the testicles have shrunken after long-term testosterone use, they will likely begin to enlarge and start their testosterone production shortly after HCG therapy is instituted. HCG jump-starts your testes to produce testosterone and to increase their size.

HCG can be extracted from pregnant women’s urine or through genetic modification. The product is available by prescription under the brand names Pregnyl, Follutein, Profasi, and Novarel. Novire is another brand but it is a product of recombinant DNA. Compounding pharmacies can also make HCG by prescription in different vial sizes. Brand names of HCG in regular pharmacies cost over $100 per 10,000 IUs.  The same amount of IUs cost around $50 in compounding pharmacies. Many insurance policies do not pay for HCG since they consider its use for testicular atrophy while on TRT an off label use. So, most men using it pay for it themselves and get it from compounding pharmacies that sell it a lot cheaper.

HCG is dispensed as a powder contained in vials of 3,500 IUs, 5, 000 IUs or 10, 000 IUs (depending on the compounding pharmacy, these amounts may vary). You can call compounding pharmacies and have them make vials for you with different IU amounts, though. These are usually accompanied by another vial of 1 mL (or cc) of bacteriostatic water to reconstitute the powder into a liquid solution. Bacteriostatic water (water with a preservative that is provided with the prescription) is mixed in with the powder to reconstitute, or dissolve, it before injection. This type of water can preserve the solution for up to 6 weeks when refrigerated. Some patients do not use the 1 mL water vials that come with the commercially (non compounded) available product and instead get their doctors to prescribe 30 cc bottles of bacteriostatic water so that they can dilute the HCG down to a more workable concentration that is more practical for men using lower doses of HCG weekly.

HCG is given as an injection under the skin or intramuscularly (there is still debate on which method is best). The number of IUs per injection will depend on how much bacteriostatic water you add to the dry powder vial. If you add 1 mL to a 5,000 IU powder vial, then you will have 5,000 IUs per mL, so 0.1 mL would be 500 IUs. If you add 2 mL to the 5,000 IU dry powder vial, then you will have 2,500 IUs/mL; 0.1 ml (or cc) in an insulin syringe will equal 250 IUs. If you need to inject 500 IUs, then you inject 0.2 ccs of this mixture. Table 3 provides dilution volumes at different HCG powder/water proportions.

Ultra-fine needle insulin syringes are used to inject HCG under the skin, making this very easy to take even for the needle-phobic. Typical sizes are:

•          1 ml, 12.7 mm long, 30 gauge and

•          0.5 ml, 8 mm, 31 gauge syringes.

Syringes require a separate prescription. Some compounding pharmacies will automatically include them with the shipment, but do not forget to ask them. Never use the syringe that you used for injecting the bacteriostatic water into the powder for injecting yourself; the needle will be dull (I usually use a regular 23 gauge, 1 inch, 3 ml syringe to load up the water). Remember that you also need alcohol pads to clean the injection area and the tip of the vial. Typical injection sites are the abdominal area close to the navel or in the pubic fat pad. Pinch a little of fat on your abdominals and inject into that pinched area, then massage with an alcohol pad. Discard syringes into the sharps container that can be provided by your pharmacy.

As I mentioned before, compounded HCG is a lot cheaper than the commercially available pharmaceutical products. Also, it is sometimes difficult to find commercially available HCG in regular pharmacies.

A review of the literature reveals a wide range of doses of HCG used and that there is very little agreement among physicians. For male infertility, doses range from 1250 IU three times weekly to 3000 IU twice weekly (these studies did not include men on testosterone replacement).

How long does the boost in testosterone last after an injection of HCG? A study looked into that and also tried to determine if high doses would be more effective at sustaining that boost. The profiles of plasma testosterone and HCG in normal adult men were studied after the administration of 6000 IU HCG under two different protocols. In the first protocol, seven subjects received a single intramuscular injection. Plasma testosterone increased sharply (1.6 ± 0.1-fold) within 4 hours. Then testosterone decreased slightly and remained at a plateau level for at least 24 hours. A delayed peak of testosterone (2.4 ± 0.3-fold) was seen between 72–96 hours. Thereafter, testosterone declined and reached the initial levels at 144 hours. In the second protocol, six subjects received two intravenous (IV) injections of HCG (5-8 times the dose given by injection to the first group) at 24-hour intervals. The initial increment of plasma testosterone after the first injection was similar to that seen in the first protocol despite the fact that plasma HCG levels were 5–8 times higher in this case. At 24 hours, testosterone levels were again lower than those observed at 2–4 hours and a second IV injection of HCG did not induce a significant increase. The delayed peak of plasma testosterone (2.2 ± 0.2-fold of control) was seen about 24 hour later than that in the first protocol. So, this study shows that more is not better when dosing HCG. In fact, high doses may desensitize Leydig cells in the testicles.  It also showed that testosterone blood levels peak not once but twice after HCG injections.  I wish they had studied a lower dose than 6000 IU since very few physicians prescribe this high dose.

HCG may not only boost testosterone but also increase the number of Leydig cells in the testicles. It is well known that Leydig cell clusters in adult testes enlarge considerably under treatment with HCG. However, it has been uncertain in the past whether this expansion involves an increase in the number of Leydig cells or merely an enlargement of the individual cells. A study was performed in which adult male Sprague-Dawley rats were injected subcutaneously daily with 100 IU HCG for up to 5 weeks. The volume of Leydig cell clusters increased by a factor of 4.7 during the 5 weeks of HCG treatment. The number of Leydig cells (initially averaging 18.6 x 106/cm3 testis) increased to 3 times the control value by 5 weeks of treatment.

Currently there are no HCG guidelines for men who need to be on testosterone replacement therapy and want to maintain normal testicular size. A study that used 200 mg per week of testosterone enanthate injections with HCG at doses of 125, 250, or 500 IU every other day in healthy younger men showed that the 250 IU dose every other day preserved normal testicular function (no testicular size measurements were taken, however). Whether this dose is effective in older men is yet to be proven. Also, there are no long-term studies using HCG for more than 2 years.

Due to its effect on testosterone, HCG use can also increase estradiol and DHT, although I have not seen data that shows if this increase is proportional to the dose used.

So, the best dose of HCG to sustain normal testicular function while keeping estradiol and DHT conversion to a minimum has not been established.

Some doctors are recommending using 200–500 IUs twice a week for men who are concerned about testicular size or who want to preserve fertility while on testosterone replacement. Higher doses, such as 1,000–5,000 IUs twice a week, have been used but I believe that these higher doses could cause more estrogen and DHT-related side effects, and possibly desensitize the testicles for HCG in the long term. Some doctors check estradiol levels a month after this protocol is started to determine whether the use of the estrogen receptor modulators tamoxifen (brand name: Nolvadex) or anaztrozole (brand name: Arimidex), is needed to counteract any increases in estradiol levels. High estradiol can cause breast enlargement and water retention in men but it is important at the right blood levels to maintain bone and brain health.

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Shippen’s Chorionic Gonadotrophin Stimulation Test (for males under 75 years of age)

Even though there seems not be an accepted and clinically proven protocol to dose HCG, Dr. Eugene Shippen (author of the book “The Testosterone Syndrome”), has developed his own after his own experiences. Most doctors do not follow this protocol but I am showing it here since I get a lot of questions about it.  I have never used this protocol myself since I have been on testosterone replacement for over 15 years.

Dr.  Shippen  has  found  that  a  typical  treatment  course  for  three weeks  is  best  for  determining  those  individuals  who  will  respond well  to  HCG  treatment.  It  is  administered  daily  by  injection  500 units subcutaneously, Monday through Friday for three weeks.   The patient  is  taught  to  self  administer  with  50  Unit  insulin  syringes with  30  gauge  needles  in  anterior  thigh,  seated  with  both  hands free to perform the injection. Testosterone, total and free, plus E2 (estradiol) are measured before starting the protocol and on the third Saturday after 3 weeks of stimulation (he claims that salivary testing may be more accurate for adjusting doses). Studies have shown that subcutaneous injections are equal in efficacy to intramuscular administration.

By measuring the effect on his HCG protocol on total testosterone, he identifies candidates that require testosterone replacement versus those who just require having their testicles “awaken” with HCG to produce normal testosterone. I am yet to see any data that substantiates his approach, however.

Here is how he determines Leydig (testicular) cell function:

1.   If the HCG protocol causes less than a 20% rise in total testosterone he suggests poor testicular reserve of Leydig cell function (primary hypogonadism           or eugonadotrophic    hypogonadism  indicating combined central and peripheral factors).

2.   20-50% increase in total testosterone indicates adequate reserve but slightly depressed response, mostly central inhibition but possibly decreased testicular response as well.

3.  More than 50% increase in total testosterone suggests primarily centrally mediated depression of testicular function.

He then offers these options for treatment for patients depending on the response to HCG and patient determined choices.

1.   If there is an inadequate response ( 20%), then replacement with testosterone will be indicated.

2.   The area in between 20-50% will usually require HCG boosting for a period of time, plus natural boosting or “partial” replacement options.

I   am   yet   to   see   what   he   means   with   natural   boosting!

Dr.  Shippen  believes  that  full  replacement  with  testosterone  is always  the  last  option  in  borderline  cases  since  improvement over time may frequently occur as the testicles’ Leydig cell regeneration may actually happen. He claims that much of this is age dependent. Up to age 60, boosting is almost always successful. In the age range 60-75 is variable, but will usually be clear by the results of the stimulation test. Also, disease related depression of testosterone output might be reversible with adequate treatment of the underlying process  (depression,  obesity,  alcohol,  deficiency, etc.) He claims that this positive effect will not occur if suppressive therapy is instituted in the form of full testosterone replacement.

3.   If there is an adequate response of more than 50% rise in testosterone, there is very good Leydig cell reserve. HCG therapy will probably be successful in restoring full testosterone output without replacement, a better option over the long term and a more natural restoration of biologic fluctuations for optimal response. But I am yet to see any data on long term use of HCG used in this approach! (I invite researchers to do such studies)

4.   Chorionic HCG can be self-administered and adjusted according to response. In younger, high output responders (T > 1100ng/dl), HCG can be given every third or fourth day. This also minimizes estrogen conversion.  In  lower  level  responders  (600-800ng/dl),  or  those with a higher estradiol output associated with full dose HCG, 300- 500 units can be given Mon-Wed-Fri. At times, sluggish responders may  require a  higher dose  to  achieve full  testosterone response.

Dr. Shippen believes in checking salivary levels of free testosterone on the day of the next injection, but before the next injection to determine effecacy  and  to  adjust  the  dose  accordingly.    He claims  that  later  as  Leydig  cell  restoration  occurs,  a  reduction in  dose  or  frequency  of  administration  may  be  later  needed.

5.   He recommends to monitor both testosterone and estradiol levels to assess response to treatment after 2 - 3 weeks after change in dose of HCG as well as periodic intervals during chronic administration. He claims that salivary testing will better reflect the true free levels of  both  estrogens  and  testosterone.  (Pharmasan.com  and  others) Most insurance companies do not pay for salivary testing.  Blood testing is the standard way to test for testosterone and estradiol.

6.   Except for reports of antibodies developing against HCG (he mentions that he has never seen this problem), the claims that there are no adverse effects of chronic HCG administration.

Dr. Shippen’s book was published in the late 90’s.   I know of no physician that uses his protocol.  I have no opinion on its validity.  The idea that testicular function can be improved with cycles of HCG in men with low testosterone caused by sluggish yet functioning Leydig cells is an interesting concept that needs to be studied. I guess that since this protocol requires very close monitoring, many doctors have avoided using it. The off label nature of the protocol’s use of HCG can also make it expensive for patients who will have to pay cash for its use and monitoring.

A very well known doctor in the field of testosterone replacement, Dr. John Crisler (www.allthingsmale.com), recommends 250  IU of HCG twice per week for all TRT patients, taken the day of, along with the day before, the weekly testosterone cypionate injection. After looking at countless lab printouts, listening to subjective reports from patients, and learning more about HCG, he reports to be shifting that regimen forward one day. In other words, his patients who inject testosterone cypionate now take their HCG at 250 IU two days before, as well as the day immediately previous to, their weekly intramuscular shot. All administer their HCG subcutaneously, and dosage may be adjusted as necessary (he reports that rarely more than 350 IU twice weekly dose is required).

For men using testosterone gels, the same dose every third day has anecdotally helps to preserve testicular size (the dose of the gel has to be adjusted after a month of HCG to compensate for the increased testosterone caused by HCG).

Some doctors believe that stopping TRT for a few weeks in which only 1000- 2000 IU HCG weekly is used provides a good way to stimulate testicular function without having to use HCG continuously. I have not seen any data to support this approach. Others believe that cycling HCG on and off while maintaining TRT may prevent any desentization of testicular Leydig cells to HCG.  Again, no data or reports have been published on this approach.

Some men have asked me why we cannot use HCG solely to make our own testicles produce testosterone without the use of TRT along with it. According to Dr. Crisler, using HCG as sole testosterone replacement option does not bring the same subjective benefit on sexual function as pure testosterone delivery systems do—even when similar serum androgen levels are produced from comparable baseline values. However, supplementing the more “traditional” transdermal, or injected options, testosterone with the correct doses of HCG stabilizes blood levels, prevents testicular atrophy, helps rebalance expression of other hormones, and brings reports of greatly increased sense of well-being and libido.  But in excess, HCG can cause acne, water retention, moodiness, and gynecomastia (breast enlargement in men).

Many men have complained that their doctors do not know about HCG and how to use it (I do not blame doctors for being confused!). Some spend a lot of time trying to find doctors to feel comfortable prescribing it. One good way to find out what doctor in your area may be currently prescribing it is to call your local compounding pharmacies to ask them what doctors call them for their patients’ prescriptions.

If you decide (with the agreement of your doctor) that you want to use HCG with your TRT regimen at 500 IU per week, then you will need 2000 IU per month. I personally do not like to have diluted HCG sitting in my fridge for over six weeks (HCG may degrade with time after mixed in with bacteriostatic water even when refrigerated). So, a 3000 or 35000 IU vial should suffice for 6 weeks.

Your doctor can call in the following prescription to a compounding pharmacy (shop around for best prices. I use APSmeds.com):

Human Chorionic Gonadotropin, 3500 IU (or any other IU amount) vial, #1, 3 refills, as directed

Every 5 weeks, remember to call the compounding pharmacy to get the next shipment of HCG so that you do not run out.

After reading this section, you probably agree with me that using HCG requires a lot of discipline since you have to remember to inject it weekly in addition to your weekly or bi-weekly testosterone injection. But I know of many men who have that type of commitment since they do not want testicular size reduction. And many of us may just be fine with our reduced testicular size as long as testosterone is actually doing its job in improving our sex drive. And some lucky men do not get testicular atrophy at all on testosterone (those with large testicles to start with usually do not seem to complain about shrinkage as much as men starting with smaller testicular size before TRT). So it is a personal decision at the end!

As you will read in the section “HPGA dysfunction” HCG is also used in a protocol in combination with clomiphene and tamoxifen to attempt to bring the body’s own testosterone production back to normal when someone needs to stop testosterone or anabolic steroids after long-term use. This protocol only works for those who started testosterone or anabolic steroids at normal baseline testosterone levels (bodybuilders and athletes) and it is not intended to work in those of us who had testosterone deficiency (hypogonadism) to start with.

As you can tell, there is no agreement on the correct dose and frequency of HCG.   I really hope that researchers in the endocrine field compare different protocols in a controlled manner so that we can settle this issue once and for all. I encourage pharmaceutical companies to seek approval for using HCG for prevention of testicular atrophy in men using TRT. This new indication can prove to be lucrative as the TRT market grows over 2 billion dollars a year in the United States as more men become aware of hypogonadism treatment options.

PERSONAL COMMENT: I have used HCG to reverse testicular shrinkage and it works extremely well not only for that purpose but also for boosting sexy drive. I do have to remind myself that as soon as I stop using it, testicular atrophy will recur.  I have recently started using it in small doses (250 IU twice a week subcutaneously) which seems to be a good maintenance regimen for me.  I get my HCG from compounding pharmacies at $70 per 10,000 IUs since the pharmaceutical commercial products are too expensive and rarely paid by insurance for testicular atrophy. I remind men that HCG can increase your estradiol and DHT blood levels, so it is important to have your doctor retest you for both of these values after you start. Lowering testosterone dosage may be required when using HCG along side with TRT since HCG can have an additive effect on testosterone blood levels. But we need so much more data on HCG to stop making assumptions and using protocols that are endorsed by anecdotal information.

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