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.

1. Therapeutic Hormones:
The story till date
Subject: PharmaceuticalBiotechnology
Assignment # 01
Submitted By: Ahmed Madni
RegistrationNo.:SP14-BTY-011
Submitted to: Dr. Fazli Wahid
Submitted date: 29th
-Sep-2016

2. 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………………………………………….

3. 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

4. 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

5. 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.

6. 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

7. 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

8. 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

9. 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.

10. It is a member of the tachykinin family of neuropeptides that are characterized by a
common carboxyl-terminal motif: Phe-X-Gly-Leu-Met-NH 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
substance-P-related 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
TACR3-selective antagonists have generally been in the CNS field (for example,

11. 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 TACR3-selective peptide agonist, senktide, was developed by systematic
methylation of the peptide bonds in a truncated version of the TACR1-selective
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

12. iv. Kisspeptin production (Metabolic hormone)
Kisspeptins are members of a family of peptide hormones known as RF-amides, which
are characterized by an Arg-Phe-NH carboxyl-terminal 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 carboxyl-terminal peptides of 14, 13 and 10
amino acids, all of which are biologically active. The 10 amino acid peptide (Kp-10) has
full intrinsic biological activity. However the 54 or 52 amino acid peptides have longer
half-lives and therefore increased LH-releasing activities than the shorter forms in vivo.
Importantly, neurons that express kisspeptin also express steroid hormone receptors.
Kp-10 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.

13. 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