Therapeutic Hormones: The story till date

Subject: Pharmaceutical BiotechnologyAssignment # 01

Submitted By: Ahmed MadniRegistration No.: SP14-BTY-011Submitted to: Dr. Fazli WahidSubmitted date: 29th-Sep-2016

Therapeutic Hormones: The story till date

Contents Page No.

I. Introduction………………………………………..

II. History of Hormone therapy……………………...

III. Some common hormones and their

function……………………………………………..

IV. Hormones as therapeutic agent…………………...

V. Conclusion………………………………………….

VI. References………………………………………….

Therapeutic Hormones: The story till date

Introduction

Therapeutic hormones are the hormones that are synthetic or naturally produced and used

in hormone related disease. Hormones are the substances that are produced naturally in

the body by the endocrine gland. Hormones act as chemical messengers and help in

control of the activity of the cells or organs. Hormone therapy works by altering the

production or activity of particular hormones in the body. The type of hormone therapy is

being used depends upon type of disease being treated.

History of Hormone therapy

The first known preparations were made by Chinese people from dried human urine of

teenager. The urine of teenagers was containing high content of sex hormones. In 1700’s

and 1800’s scientists grinded up the ovaries, testicles and organs from animals and put

them into different potions. It took years before they were able to chemically extract the

active ingredients. In 1900s, a patent medicine company named Merck, produced

estrogen from the dried ovaries of cows. It was given to women having menopausal

symptoms. By the 1920s a derivative of amniotic fluid from pregnant cows was

developed. In the 1930’s, the hormone named progesterone was first recognized. But the

production was expensive, requiring huge amounts of corpora lutea an endocrine tissue

from pigs. The main problem was that most of the oral progesterone was metabolized in

the liver before it reached to the general circulation where it was utilized. The first orally

effective estrogen was introduced by Ayerst Labs (now Wyeth Pharmaceuticals) which

derived from the late pregnancy urine of women as it contains very large amounts of the

estrogen estriol. At the same time, a company of Germany named Shering, had developed

a similar product from human pregnancy urine. Unluckily, these oral estrogens were not

successful because they were expensive, requiring enormous amounts of urine from

pregnant women.

Then the companies switched their attention to horse urine which was abundant, less

expensive and readily available. Pregnant mares (females) proved to be the best source

for the huge volumes of urine required for production. The urine from stallions (males)

had the most potent estrogens, but collection wasn’t easy.

In 1949, Wyeth-Ayerst introduced a drug composed of estrogenic compounds called

Premarin (Pregnant mare’s urine). This drug had shown good results for women that

resulted relief from hot flashes, vaginal dryness, night sweats and depression. By the

early 1970’s, Premarin was the gold standard treatment for menopausal symptoms. But in

1975 clinical studies reported a link between Premarin and uterine cancer. A few studies

indicated that uterine cancer could be prevented if progestins, progesterone-like drugs,

were prescribed along with Premarin. The basis for this was unopposed estrogen, a term

used to describe estrogen that was not counter-balanced with progesterone. In the next

few years, Wyeth further made the most of this combination with the introduction of two

new estrogen/progestin drugs, Prempro (conjugated estrogens/medroxyprogesterone

acetate) and Premphase (is a medicine containing the hormones, estrogen and progestin).

In 1993, the National Institutes of Health conducted a drug trial called the Women’s

Health Initiative (WHI) to discover the effects of these estrogen/progestin drugs on the

long-term health of menopausal women. Specifically designed to examine the prevention

of heart disease and hip fractures, and associated change in risk for breast and colon

cancer, the study did not look at the short-term risks and benefits of treating menopausal

symptoms. In 2000 and 2001, investigators found increases in heart attacks, strokes and

blood clots in the study participants. In 2002, the number of breast cancers had increased

to the point that the study was suddenly stopped. Results showed that women taking these

drugs had increased risk of heart disease, breast cancer, stroke and blood clots. In 2003,

additional effects reported an increased risk of dementia or Alzheimer’s disease.

During the time period 1949-2002, when estrogen/progestin drugs (Hormone

Replacement Therapy - HRT) were dominating the market, bioidentical hormones were

also being manufactured. In the 1940s, an easy and inexpensive way to produce

bioidentical progesterone and estrogen was discovered. Diosgenin, a steroid precursor

chemical, was extracted from wild yams and converted into bioidentical hormones. They

were easily and cheaply produced, the pharmaceutical companies had no interest in

bioidentical hormones because they could not be proved and so therefore, were not

profitable.

In the 1970s, studies reported that Premarin was giving to women having uterine cancer.

To neutralize the negative effects of Premarin and prevent uterine cancer, progesterone

was needed. Instead of bioidentical progesterone using, pharmaceutical companies used

Provera, a patented progesterone-like drug (progestin).

Even History shown these estrogen/progestin drugs would cause disorder on women for

several decades, it was not until 2002 that the WHI reported significant increases in blood

clots, cancer, heart disease and stroke. All the while, bioidentical hormones that were

readily available at that time were rejected.

After the results of the WHI were published, the public was informed that hormones were

carcinogenic. This caused alarm into the hearts of women and the use of HRT dropped

dramatically. There was no difference made between HRT and BHRT. The message was

simply that hormones were dangerous. But surprisingly, there were still doctors who

ignored the WHI results and prescribed HRT with its documented health risks.

The negative results of the WHI were on HRT, not BHRT. Since bioidentical hormones

have the same molecular structure of the hormones that our body makes, it makes sense

to use them. Our body identifies them as human-identical hormones and metabolizes

them just as if you had made them. As information about BHRT became available to

women, interest in BHRT increased significantly. BHRT had never been shown to cause

harm.

The HRT didn’t turn down so easily and BHRT has been systematically attacked by the

pharmaceutical companies and the medical organizations they support. It is being said

that even HRT has significant health risks, at least those risks are known, and this is

better than BHRT, with yet unknown risks.

History and science, however, have shown these claims are untrue, and that BHRT is

safer than HRT. Bioidentical hormones have been produced and used safely by women

for over 75 years. There is not one study that reports BHRT causes harm. In fact, the

most recent data of over 200 studies on BHRT shows that bioidentical hormones are safe

and effective.

Today, a few bioidentical hormones are sold by pharmaceutical companies as branded

products such as Prometrium (progesterone). The branding name is change but the

bioidentical hormones are the same hormones. Other bioidentical hormones have been

incorporated into patented medicines by pharmaceutical companies. It’s not the actual

bioidentical hormone that is patented, because a naturally occurring substance cannot be

different but the method for delivery such as patch, cream, gel, etc. is different.

Some common Hormones and their function

o Somatostatin: Inhibitory hormone that prevents release of hormones such as growth

hormone from the anterior pituitary

o Gonadotrophin releasing hormone (GnRH): Stimulates release of follicle

stimulating hormone (FSH) and luteinising hormone (LH) from the anterior pituitary

o Corticotrophin releasing hormone (CRH): Stimulates adrenocorticotrophic

hormone (ACTH) release from the anterior pituitary

o Thyroxine (T4): Acts to regulate the body’s metabolic rate

o Tri-iodothyronine (T3): Acts to regulate the body’s metabolic rate

o Vasopressin (anti-diuretic hormone, ADH): Acts to maintain blood pressure by

causing the kidney to retain fluid and by constricting blood vessels

o Oxytocin: Causes ejection of milk from the milk ducts and causes constriction of the

uterus during labour

o Insulin: Acts to lower blood glucose levels

o Glucagon: Acts to raise blood glucose levels

o Gastrin: Promotes acid secretion in the stomach

o Serotonin (5-HT): Causes constriction of the stomach muscles

o Erythropoietin: Stimulates red blood cell development in the bone marrow

Hormone as therapeutic agent

i. Somatostatin hormone production (Growth Hormone)

The presence of somatostatin in hypothalamic extracts was first established by Krulich

and McCann. In 1973, it was isolated from sheep hypothalamic by Brazeau and his

companions. The tetradecapeptide which inhibited the release of growth hormone (GH)

in vitro and in vivo, and which they named somatostatin. They also established its

structure. P Subsequently, Andrew and his team isolated and determined the structure of

porcine somatostatin, the structure of which was identical to ovine. They also isolated a

larger form of somatostatin from pig hypothalami with amino-terminal extension, that is

somatostatin 28. Somatostatin 14 and 28 also suppress the secretion of glucagon and

insulin and decrease the release and action of gastrin and other GI hormones.

Somatostatin is present in discrete cells of the pancreas, gastric mucosa, duodenum and

other tissues, and may play an important role in the regulation not only of the pituitary,

but also of the endocrine pancreas and gastrointestinal tract. Somatostatin appears to be

an endogenous growth inhibitor. Somatostatin was synthesized by I severa groups.

Somatostatin itself is of little therapeutic value because it has multiple actions and a short

biological half-life. However, their group and others produced superactive analogs of

somatostatin with prolonged and more selective activity.

ii. Bombesin antagonist (Cancer Treatment hormone)

Bombesin/gastrin releasing peptide (GRP) antagonists. Another class of antitumor

compounds could consist of antagonists of bombesin/GRP. Bombesin contains 14 amino

acids and was first found in the skin of the frog Bombina bombintf2 and in the stomach

and brain. Gastrin releasing peptide, which has 27 amino acids, is the mammalian

equivalent of bombesin f and is found in the stomach and gut. Both bombesin and GRP

are also found in the hypothalamus. Since bombesin and GRP are produced by various

cancers, such as small cell lung carcinoma and breast and pancreatic cancer and could act

as autocrine growth factors, the development of hormone therapy based on bombesin

antagonists should be considered.

Andrew and his team have synthesized more than 200 bombesinl GRP receptor

antagonists with different modifications at positions 6, 7, 13 and 14, and a pseudopeptide

bond at positions 13 and 14. These antagonists inhibit the binding of labeled GRP(14-27)

and Tyr4 bombesin to the receptors, and are also active in vivo.

In nude mice with transplanted hormone-dependent human prostate cancer PC-82,

bombesin antagonist RC-3095 and the combination of [0-Trp6] LH-RH and RC-160

caused a greater inhibition tumor growth than [O-Trp6] LH-RH or RC-160 alone.

Similarly, in nude mice bearing xenografts of the androgen-independent human prostate

cancer cell lines PC-3 or DU-145, tumor volumes and weights were significantly reduced

by somatostatin analog RC-160 and bombesin RC_3095. In all three human prostate

cancer models, administration of RC-160 or RC-3095 produced a significant down-

regulation of EGF receptors. Our results suggest that somatostatin analog RC-160 and

bombesin/GRP antagonist RC-3095 can inhibit the growth of androgen independent

prostate cancer when the therapy is started an early stage of tumor development.

iii. Neurokinin B (Neuro-hormone)

Neurokinin B belongs to the tachykinin family. Neurokinin B may play an important role

in the olfactory and neuroendocrine processing information. Neurokinin B has great

effect and has neruomodulatory roles in various brain functions.

It is a member of the tachykinin family of neuropeptides that are characterized by a

common carboxylterminal motif: PheXGlyLeuMetNH and also includes Substance P

(neuropeptide, acting as a neurotransmitter and as a neuromodulator) and Neurokinin A

These carboxyl terminal-amidated peptides are derived from two preprotachykinin

(precursor proteins that are modified into tachykinin peptides through alternative slicing

and post-translational modifications) genes the PPT-A (Plasma Protein Therapeutics

Association) gene encodes the sequences of Substance P, Neurokinin A, and

neuropeptide K and the PPT-B gene encodes the sequence of Neurokinin B. Neurokinin

B stimulate the production of immunoglobulins in peripheral B lymphocytes. This

conditional response to Neurokinin B is likely due NK-3 receptors present only following

co-culture and activation.

Receptor affinities of the different tachykinins are specified by variations in the amino

terminal domain of the peptide. Neurokinin B was first identified in the 1980s as a

substancePrelated peptide in porcine spinal cord. Neurokinin B interacts with all three

mammalian GPCR tachykinin receptors (TACR1, TACR2 and TACR3) but has highest

selectivity for TACR3. This tachykinin receptor, which is selective for neurokinin B, was

first identified through binding studies in mammalian CNS and functional studies using

guinea pig ileum, leading to the cloning of human TACR3.

A number of tachykinin analogues exist, and the majority of these have selectivity for

TACR1 or TACR2. However, some analogues have been developed that are highly

selective for TACR3. As the importance of neurokinin B in the neuroendocrine control of

reproduction has only become clear in the past 5 years, the therapeutic targets for

TACR3selective antagonists have generally been in the CNS field (for example,

schizophrenia, anxiety, pain, inflammation) and also in some pulmonary diseases (for

example, chronic obstructive pulmonary disease) and gastrointestinal tract diseases (for

example, irritable bowel syndrome). The development of these analogues fortuitously

provides an opportunity to utilize these agents to delineate the role of neurokinin B in

reproductive neuroendocrinology and as potential therapeutics in this area.

The first TACR3selective peptide agonist, senktide, was developed by systematic

methylation of the peptide bonds in a truncated version of the TACR1selective

tachykinin, substance P. Senktide, in which the phenylalanine at position 8 is methylated,

was found to have very high selectivity for TACR3 compared with neurokinin B. In

addition, this modified peptide also had much higher metabolic stability than the native

tachykinins, making it a useful experimental tool. An analogue of neurokinin B in which

the valine at position 7 has been replaced with methylphenylalanine in a similar way also

retains high affinity for the TACR3 and has improved selectivity for TACR3 over the

other tachykinin receptors. Replacing valine at position 7 of neurokinin B with proline

also improves selectivity for the TACR3. Screening and optimization of a dipeptide

library has also led to the development of ‘peptoid’ antagonists, with high selectivity for

TACR3.

Receptor Gene Preferred ligand

NK1 TACR1 substance P

NK2 TACR2 neurokinin A

NK3 TACR3 neurokinin B

iv. Kisspeptin production (Metabolic hormone)

Kisspeptins are members of a family of peptide hormones known as RFamides, which are

characterized by an ArgPheNH carboxylterminal motif. These peptides are involved in

numerous physiological and pathophysiological processes including control of food

intake, pain, inflammatory responses, development and metabolism.

Kisspeptin was initially termed metastin owing to its activity in inhibiting metastasis of

melanoma cells. The KISS1 gene transcribes a 145 amino acid poly peptide with a signal

sequence, followed by a 119 amino acid sequence that is processed to a 54 amino acid

peptide in humans. The human 54 amino acid peptide and rodent 52 amino acid peptide

are further proteolytically processed to carboxylterminal peptides of 14, 13 and 10 amino

acids, all of which are biologically active. The 10 amino acid peptide (Kp10) has full

intrinsic biological activity. However the 54 or 52 amino acid peptides have longer half-

lives and therefore increased LHreleasing activities than the shorter forms in vivo.

Importantly, neurons that express kisspeptin also express steroid hormone receptors.

Kp10 is a potent stimulator of LH, FSH and gonadal steroid secretion when administered

both centrally and systema tically. Kisspeptin stimulation of gonadotropins is ablated

with help of GnRH antagonist, demonstrating that kisspeptin acts through the stimulation

of GnRH secretion.

Conclusion

Hormones are chemicals made in the body. They control how cells and organs work.

With respect to hormone therapies, the only significant factor is whether the molecular

structure of the replacement hormone exactly matches that of the natural hormone it is

replacing. Our body identifies them as human-identical hormones and metabolizes them

just as if our body had made them. As information about BHRT became available,

interest in BHRT increased significantly. Now a day, Pharmaceutical companies are

producing the hormone based drug which is containing same molecular formula but

having different brand names. And their delivery to the body is also different.

References

Andrew V Schally (1994) , “Hypothalamic hormones: from neuroendocrinology to

cancer therapy” , Anti-Cancer drugs, 5, pp. 115-130, Endocrine, Polypeptide and

Cancer Institute, Veterans Affairs Medical Center, New Orleans, LA 70146, USA.

Robert P. Millar and Claire L. Newton, “Current and future applications of GnRH,

kisspeptin and neurokinin B analogues”, Endocrinology, Nature reviews, volume 9.

http://www.genscript.com/peptide/RP10517-Neurokinin

NH2_Tachykinin_family.html

http://www.endocrinesurgeon.co.uk/index.php/what-are-the-functions-of-the-

different-types-of-hormone

http://www.demontecentre.com/hormone-replacement/history-of-hormone-

therapy.html