What Is the Main Hormone in the Male Reproductive System ? Testosterone

Lyn smadipharmacology / Sheet #13April 3, 2014

Androgens

What is the main hormone in the male reproductive system ? testosterone

Testosterone is converted todihydrotestosterone which is the most potent hormone in the male hormone system.

We talked last time about different functions of androgens, and when we know their functions we can know their therapeutic uses:

1)Stimulate and maintain the male reproductive tract

2)Important in the production of red blood cells through Erythropoiesis, so they are important in the production of EPO or erythropoietin.

3)They have anabolic effects; increasing the exercise duration, the muscle’s strength; they increase the muscle mass, they have a positive nitrogen balance, but they have a side effect that they cause more retention of sodium and electrolytes so males have more tendency to develop hypertension than females, this is also a side effect when using these hormones as drugs.

**We talked about the anabolic use of steroids, and we said that some people like athletes use it to increase their capability in running for long time, and other people such as body builders use it to increase their muscle mass. This is not a good use of steroids, it is considered as a form of abuse, because the doses that they use for these purposes are 10-50 times higher than the therapeutic doses (used to treat certain medical conditions).

**now we’ll talk about testosterone and dihydrotestosterone.

Testosterone

-Is the principle natural androgen.

-Is Synthesized in testes in leydig cells

-the main regulator of its synthesis is the hormone of the pituitary Luteinizing hormone.

Dihydrotestosterone (DHT)

-testosterone is converted by 5α-reductase to DHT, which is more potent than testosterone.

-It is essential for the formation of the male external genitalia, and the secondary male characteristics.

** there is a condition called Pseudohermaphroditism:

If a person has the genes of a male, so he has the XY chromosomes but he has the sex characteristics of the female and usually this doesn’t show apparently until after puberty, so when this person is a child usually his parents can’t differentiate that but later on after puberty because he needs the expression of the hormone5α-reductase. And these patients in this condition have deficiency in 5α-reductase, so they don’t have DHT which is important in the expression of male external genitalia and male secondary sex characteristics. And this is what is called the third gender; they are in between males and females. One reason for that is because they have a deficiency in the hormone 5α-reductase.

**we want to talk about the uses ofthe testosterone and its derivatives.

-We can use it for hypogonadism, so these patients with hypogonadism have lowlevels of testosterone due to different reasons; it can happen prepubertal or postpubertal. And if it was prepubertalusually the therapy is to give them testosterone since it is easily absorbed in the body so we give them testosterone esters either testosterone Enanthate, testosterone Cypionate ortestosterone Propionate and these are available as injections. If the deficiency happens after puberty –postpubertal- we can give them oral therapy, in oral therapy modifications are done so it can be absorbed, if the methyl group is added it will be absorbed in lipids so it will be absorbed in intestines. So we can give them methyltestosterone. Testosterone in the form of a patch, patients apply the patch on their back or to the scrotum and there will be release of the hormone, and because in the skin we have high levels of 5α-reductase testosterone is converted to the potent form which is DHT.

-Other use for androgens is the production of red blood cells so we can use it for anemia because it stimulates erythropoietin formation by the kidney. It can be used in anemia caused by bone marrow failure & kidney failure. But, nowadays we have a recombinant form of erythropoietin (erythropoietin is a protein and it’s hard for us to get it before the recombinant DNA technology, but now we can clone the bacteria and grow this human hormone in them and we get the erythropoietin), so we can inject humans by recombinant EPO so it is a recent substitute for androgen therapy for anemia.

-It has some antagonizing characteristics of certain molecules in our body that enhances the osteoclast activity, so androgens will increase the formation of bone. But this subject is somewhat controversial, some people say increased androgens increase osteoporosis risk and some people say it can aid up; it depends on the dose. It has potential therapeutic uses for osteoporosis but it’s not used clinically yet.

Note: the body mainly to hormones reacts differently with different doses of these hormones.

-Other use for female, it can be used for breast cancer. This is also a subject for controversy, there are certain cancers that are stimulated by estrogen and they think that androgens have an antagonizing effect of estrogens that’s why they can be used to treat breast cancer but it is not used commercially or clinically yet. So these are areas of research of possible uses of androgens.

-We talked about its use and its protein anabolic agent. In certain conditions in protein wasting cases we can use androgens to increase the protein mass; it is abused in athletes, however in patients who have AIDS or certain cancers and have protein wasting we can use these androgens to increase their muscle mass.

-Note that androgen is converted to estrogen in males & females, and it depends on where in the body,so it depends on the concentration of the aromatase enzyme. So we have certain levels of testosterone in our body and not all of them are converted to estrogen. It depends on the body needs, and the tissues where testosterone can be converted to estrogen.

-In breast cancer they believe that it has antagonizing effect on the estrogen receptor. Certain breast cancers are stimulated by estrogens; we call them estrogen sensitive breast cancer.There are different types of breast cancer, estrogen modulators are used also to treat breast cancer.

There is no definite hormone or treatment for these conditions. But there are many hormones that interact and can either relieve the situation or exaggerate it. As we said in oral contraceptives, that some oral contraceptives they say that they increase the risk of the patient to develop breast cancer. So it depends on the dose and the tissue itself (the sensitivity of the receptors on that tissue).

In relation to the preparations: we have injection form, oral form and patches. The injection form: Esterified testosteronecan prolong the absorption time. Esterification with carboxylicacidincreases the polarity of testosterone and thus made it more lipid soluble, so it will enter the fat vehicle (the solution which is used in injections to dissolve the drug) easily. We have different formulations, but don’t worry about them. Just know that there are oral forms injection forms and patches. (injection form doesn’t go to the portal system at all.)

The oral form is methyl-testosterone. itis effective when given by mouth because of reduced hepatic metabolism which means that this form doesn’t get metabolized by the liver. In this form they did the little addition in order to increase its absorption and to avoid the first pass metabolism.

Testosterone by itself is not methylated and is subjected to the first pass metabolism. So we need it to be methylated to be able to give it orally.

Patches:these are applied either on the scrotum or on the back. This increases DHT concentration because of the high levels of 5α-reductase in the skin.

Side effects of androgens and it depends whether a female is taking the androgens or a male is taking the androgens. So some females could use testosterone for certain conditions, some athletes take them to increase their muscle mass and they used to use them before for anemias as well.

- Females will have virilization, so they will start to develop male secondary sex characteristics, they will have acne, coarse voice, hirsutism (is the excessive hairiness on women in those parts of the body where terminal hair does not normally occur or is minimal),and menstrual irregularities.

-The opposite happens for males taking too much of androgens. Because when they have too much of androgens more of it will be converted to estrogens so they will have feminization and that means they will have more estrogen and they can increase the size of male breast which is called gynaecomastia.

-In relation to hypertension, we talked about and we said there is increase in Na retention and more electrolytes and water retention, so more possibility to develop hypertension and more edema in people taking androgens

-People who take certain derivatives of testosterone are more prone to develop jaundice, carcinomas of the liver and hepatitis.

-Also too much testosterone can increase the LDL levels. Remember that estrogen increases HDL while progesterone decreases HDL and increases LDL.

-And too much testosterone increases the chance to develophyperplasia of the prostate.

There are certain drugs that are considered anti androgens, not all of them directly interacting with androgen receptors. Some of them work at the synthesis level so we have: ketoconazole which is antifungal drug, spironolactone which is a K sparing diuretic and one of its side effects is gynaecomastia because it blocks one of the enzymes in the synthesis of androgens.

Indirect way of blocking androgen production is Leuprolide(as you remember from the no. one lecture: Leuprolide is GnRH agonist. Generally GnRH agonists can be given either constantly or intermittently. Leuprolide is given constantly at high dose. usually the normal rhythm is in a pulsatile pattern for the production of this hormone GnRH from the hypothalamus, and we said if we give it in the same manner that the body makes (pulsatile, low doses and in intervals), so we give a pulse and after 2 hours for example we give another pulse, then there would be stimulation in LH & FSH production. However, if we give it in a constant high dose there will be stimulation for 2 weeks then suppression. We want to use it to treat conditions such as prostate cancer, when we have too much testosterone stimulating the prostate to grow and we want to stop this.

Another thing we use it for pharmacological castration which is reversible, we use a drug to inhibit the release of FSH & LH so no production of sperms (castration means histological removal of the testecles so no production of sperms to those who don’t want to have kids).

** other drugs related to androgens: 5α-reductase inhibitors, you remember the last time we said that this drug is used to treat male pattern boldness (boldness that happens due to problems in the androgens), and sometimes it happens in femaleswhen they have too much of DHT in the scalp of the head and when they have over expression of DHT, although it is important for the production of hair follicles but too much of it causes these hair follicles to be brittle and they don’t have very good hair formation, so this hair doesn’t grow very well (سيتساقط)and they will have boldness because of overproduction of DHT. We use an inhibitor of 5α-reductase FINASTERIDEand this is a drug used clinically to treat male pattern boldness in males and females (another name is androgenic alopecia).

Androgen receptor antagonists: flutamide is also used to stop the production of sperms as a form of contraceptive but male contraceptive.

Leuprolide

To remind u again aboutLeuprolideit can be used for hormone-responsive cancerscause it’s going to inhibit the release of LH & FSH in cancer cases such as prostate cancer or breast cancer, also in conditions where we have hyperplasia such as: endrometriosis or uterine fibrosis in females so we can use this drug to control this overproduction of hormones that make the gonads overgrow in form of hyperplasia.

It can be used in Precocious puberty, when some people reach puberty early like at 7 or 8 years and this is inconvenient for a child (for girls to have menstrual cycle that young) so they want to postpone it, and they can use this drug Leuprolideto postpone their menstrual cycle, and a lot of times they use it because when menstrual cycle starts in females the bones start to close so the girl won’t increase in stature, so some people use this drug for their girls to let them increase more in their height by postponing their menstrual cycle (the girl will increase in height a little more until she is 12 or 13).

Another use is to control ovarian stimulation in In Vitro Fertilization (IVF), they give the female hormonesto stimulate the production of eggs from ovaries, & u know in IVF usually these females for some reason (either a problem in the male or a problem in the female) are not able to conceive naturally, so they will harvest eggs then they will take male sperms’ sample, and then they will fertilize these eggs in a tissue culture in the lab, but not all of them get fertilized, that’s why they take many eggs from the female so at least 5 of them get fertilized, and then they implant them in the female and some of them will get implanted and grow to be babies, and that’s why people who make this IVF some of them will have 3 babies while others 4 or 5 babies because they harvest so many ova.(They will collect as much as they can from eggs through stimulation to ovaries to produce as much as 15 to 30 eggs). And this drug we give it to females after stimulation, and sometimes if IVF doesn’t work and the ovaries are still stimulated we give them this drug leuprolide to stop the stimulation (or to minimize it).

Some drugs we use to prevent premature ovulation; we don’t want the ova to leave the ovaries and go to uterus instead we want to harvest them from the ovaries since we can’t get them from the uterus, also to prevent this premature ovulation we can use this drug leuprolide or we can use sometimes Ganirelix (GnRH antagonist) and both of them suppress LH & FSH production.

## note that there is a surgical castration and this is where they cut the testes out in a surgical procedure, and a pharmacological castration (an alternativechoice) where they use contraceptive and the male takes this drug Leuprolide and doesn’t produce sperms (so in pharmacological castration they don’t cut the testes out but stop the production of sperms).

Now we’re going to talk about a topic that is not related to androgens estrogens but to the male reproductive system which is erectile dysfunction which is more related to the autonomic nervous system.

Erectile dysfunction:nowadays it is a major problem in males above the age of 40 because of many things that these men have (such as hypertension, diabetes & a very important risk factor is smoking).

Erectile dysfunction is the inability to achieve or maintain penile erection.

It happens for example in the United States:

-in 40% of men above the age of 40

- 70% of male above the age of 70

**There are different factors that cause this problem or increasing the risk of having it:

-Atherosclerosis

-Diabetes mellitus

-Hypertension

-Smoking

-Drug induced: certain drugs can induce it such as: beta blockers, diuretics & antidepressants.

-Sometimes this problem happens because of a trauma to the spinal cord or to the nerve supplying this tissue, which happens if the patient is subjected to operation such as prostatectomy (if the patient has a prostate cancer or prostate hyperplasia he has to go into operation to get his prostate out the doctor may injure some of the nerves that supply the penile tissue.)

Erection: is a hydraulic (ضغط مائي) pressure under Autonomic control. So we will go back to the autonomic nervous system. Please refer to the slides # 30 or page 15.

There is a cross section of the penis, and there are 2 large blood vessels called corpus cavernosum & it is under the control of sympathetic nervous system through norepinephrine (NE), NE causes its contraction,while parasympathetic nervous system (rest & digest) causes dilation of these blood vessels & erection will happen as a result of the flow of the blood. Parasympathetic is under the control of nitric oxide (NO) & other vasodilators, and NO is producedthrough 2 ways; non adrenergic non cholinergic nerve endings these produce NO directly and causes dilation of the blood vessels. There are also endothelial cells that line the blood vessels that also produce nitric oxide, and remember that these endothelial cells are stimulated by acetylcholine. This NO is a vasodilator that goes to the smooth muscle cells underneath the endothelial cells causingthem to relax and dilation will happen.

We’re going to talk about drugs that are used to treat this condition where this blood vessel is contracted rather than dilated, and these drugs increase the dilation of these blood vessels.

NO is produced either by non adrenergic non cholinergic nerve endings or by another pathway where arginine gets converted to NO & ciruline by the action of nitric oxide synthase then NO goes directly to the smooth muscle cells and binds to the enzyme activating it then NO breaks down, the enzyme is Guanylate cyclase and it forms cyclic GMP which in turns causes relaxation of the smooth muscle cells in the corpus cavernosum and dilation will happen. (NO is a gas with a very short half life almost 5 seconds). Now how cGMP causes the dilation? It activates many things in the body; certain channels, pumps, transporters and enzymes, and through them decreases the Ca entry & decreases the intracellular Ca concentration, and when there is no Ca relaxation happens while when there is high Ca concentration contraction happens.