**5. Pharmacology of hormone replacement therapy**

The pharmacology of hormone replacement therapy is of a particular interest given the complex benefit/risk balance and the importance of this treatment for women health. As illustrated in previous paragraphs, there is a wide diversity of drugs and protocols proposed for HRT. Our analysis will be limited to the pharmacology of the natural sex steroid 17β-estradiol.

#### **5.1 The route of oestradiol administration (oral versus transdermal) highlights the hepatic first pass effect**

Oral oestradiol is commonly used by women receiving HRT, being seen as a convenient and inexpensive option. In turn, following oral administration, oestradiol is subject to the firstpass effect, a term that encompasses the metabolic changes underwent by a drug before it reaches systemic circulation. This results in the use of higher doses of oestradiol (~ 1,5 mg/day) compared to parenteral routes (patch ~ 50µg/24h). Moreover, subsequent to the various metabolic changes suffered by oestrogens once absorbed in the intestinal tract, a specific profile of oestradiol metabolites and oestrogen-dependent serum parameters with particular pathophysiological implications will appear, widely different from what is observed after the use of transdermal oestradiol where the first-pass effect is avoided.

The oestradiol metabolism pathway (Raftogianis et al., 2000) is outlined in Figure 4. Rapidly after the intestinal absorption, part of oral oestradiol is converted to oestrone, a reversible reaction catalysed by 17β-hydroxysteroid-dehydrogenase (HSD), and the conversion may continue towards their inactive conjugates (i.e. sulfates and glucuronides). Subsequent to this process, the oestrone/ oestradiol ratio resulting from oral administration is significantly higher (approximately 5:1) than the one observed following transdermal administration (approximately 1:1, which is similar to the physiologic ratio found in premenopausal women)(Kuhl, 2005). Contrary to the aforementioned transformations, further phase I reactions (oxidation reactions catalysed by cytochrome P450 (CYP) enzymes) are no more reversible. The final steps in oestrogen metabolism involve the process of detoxification under the action of phase II enzymes.

The first pass effect of oestradiol results in various biological consequences (De Lignieres et al., 1986). For instance, a well known effect attributed to hepatic first pass is the decrease of IGF-1 after oral oestradiol, whereas no significant change was observed with transdermal oestrogens (Sonnet et al., 2007). Furthermore, an increased synthesis of blood coagulation factors (Caine et al., 1992) and resistance to activated protein C (Oger et al., 2003) constitute another important consequences which are directly implicated in VTE pathophysiology, one of the major adverse events of oral oestrogens.

Thus, POI patients should be informed that results from reports on HRT associated breast cancer do not necessarily apply to their case, in which treatment is intended to provide the hormones that should be physiologically present at their age (Maclaran & Panay, 2011).

These particularities of the HRT risk profile in women facing a premature cessation of the ovarian function, together with the beneficial bone effects (Farquhar et al., 2009), support the current recommendations regarding the need for HRT substitution until the average age of

The pharmacology of hormone replacement therapy is of a particular interest given the complex benefit/risk balance and the importance of this treatment for women health. As illustrated in previous paragraphs, there is a wide diversity of drugs and protocols proposed for HRT. Our analysis will be limited to the pharmacology of the natural sex

**5.1 The route of oestradiol administration (oral versus transdermal) highlights the** 

Oral oestradiol is commonly used by women receiving HRT, being seen as a convenient and inexpensive option. In turn, following oral administration, oestradiol is subject to the firstpass effect, a term that encompasses the metabolic changes underwent by a drug before it reaches systemic circulation. This results in the use of higher doses of oestradiol (~ 1,5 mg/day) compared to parenteral routes (patch ~ 50µg/24h). Moreover, subsequent to the various metabolic changes suffered by oestrogens once absorbed in the intestinal tract, a specific profile of oestradiol metabolites and oestrogen-dependent serum parameters with particular pathophysiological implications will appear, widely different from what is observed after the use of transdermal oestradiol where the first-pass effect is avoided.

The oestradiol metabolism pathway (Raftogianis et al., 2000) is outlined in Figure 4. Rapidly after the intestinal absorption, part of oral oestradiol is converted to oestrone, a reversible reaction catalysed by 17β-hydroxysteroid-dehydrogenase (HSD), and the conversion may continue towards their inactive conjugates (i.e. sulfates and glucuronides). Subsequent to this process, the oestrone/ oestradiol ratio resulting from oral administration is significantly higher (approximately 5:1) than the one observed following transdermal administration (approximately 1:1, which is similar to the physiologic ratio found in premenopausal women)(Kuhl, 2005). Contrary to the aforementioned transformations, further phase I reactions (oxidation reactions catalysed by cytochrome P450 (CYP) enzymes) are no more reversible. The final steps in oestrogen metabolism involve the process of detoxification

The first pass effect of oestradiol results in various biological consequences (De Lignieres et al., 1986). For instance, a well known effect attributed to hepatic first pass is the decrease of IGF-1 after oral oestradiol, whereas no significant change was observed with transdermal oestrogens (Sonnet et al., 2007). Furthermore, an increased synthesis of blood coagulation factors (Caine et al., 1992) and resistance to activated protein C (Oger et al., 2003) constitute another important consequences which are directly implicated in VTE pathophysiology, one

natural menopause (Vujovic et al., 2010).

steroid 17β-estradiol.

**hepatic first pass effect** 

under the action of phase II enzymes.

of the major adverse events of oral oestrogens.

**5. Pharmacology of hormone replacement therapy** 

*Various isoforms of cytochromes P450s (CYP3A, CYP1A and CYP1B families) activate estrogens during phase-1 metabolism. Oxidative metabolites, such as hydroxyestradiol and quinone derivatives, are conjugated by various phase-2 enzymes. The expression of several of these enzymes (SULTs, UGTs, GSTs and NQO1) is regulated by Nrf2. E: estradiol or estrone; CYPs: cytochrome P450s; UGTs: UDP-glucuronosyltransferase; COMT: catechol-omethyltransferase; GSTs: glutathione S-transferases; NQO1: NAD(P)H dehydrogenase, quinone 1. Phase-1 metabolism is represented by horizontal arrows. Phase-2 metabolism is represented by vertical arrows (dashed).* 

Fig. 4. Oestrogens hepatic metabolism

#### **5.2 Pharmacokinetic of oral** *versus* **transdermal oestrogens**

The pharmacokinetics of exogenous estrogens is complex and most efficacy studies of transdermal *versus* oral oestrogens have not included the measurement of oestrogens concentrations. The oral route of oestradiol administration is easy and convenient, however the hormone is extensively metabolized in the gut and the liver leading to first-pass effect and, as previously mentioned, to a high estrone/oestradiol ratio (Kuhl, 2005). On the other hand, transdermal 17β-oestradiol is well absorbed through the epidermis and produces higher parent oestrogens serum concentrations and lower metabolites ratios because it bypasses the liver. Moreover, owing to a very low bioavailability [0.1 – 12%] of oral micronized 17β-oestradiol (O'Connell, 1995), higher doses are needed for the oral route compared to transdermal administration (O'Connell, 1995; Powers et al., 1985).

Pharmacokinetic profiles of transdermal and oral oestradiol are very different with oral administration producing fluctuant concentrations compared to the more constant levels achieved with transdermal formulations (Kopper et al., 2009). Interestingly, there is no pharmacokinetic/pharmacodynamic relationship between serum levels and positive effects of oestradiol treatment. It has been clearly shown that serum level after transdermal oestradiol does not predict the outcome when treating hot flushes (Steingold et al., 1985). The precise oestradiol and oestrone concentrations required to prevent bone loss and

Pharmacology of Hormone Replacement Therapy in Menopause 327

Fig. 5. Genetic polymorphisms modulating liver metabolism and first pass effect of

stratification of thrombotic risk and identify new groups at high risk.

These pharmacogenetic studies provide new insights suggesting that liver metabolism of oestrogens may be implicated in the pathophysiology of VTE among women using HRT with oral oestrogen therapy. This original finding deserves further investigations in largest and independent series of women receiving oral 17β-oestradiol as well as other oestrogens with different metabolic pathways, not only to treat postmenopausal symptoms but also for contraception. Taking into account the proportion of women using exogenous hormone therapy, these new results may have important clinical implications to improve the

The increasing life expectancy observed during the last century, without an equivalent change in the average age of menopause, resulted in an increased number of women facing the effects of low ovarian steroids for a longer period of time. Thus, the high interest towards therapeutic options capable to alleviate menopausal symptoms and the extensive research in this field are not surprisingly. Despite the current controversies summarised here which encompass HRT use, further researches will likely improve therapeutic outcomes. In this context, pharmacogenetics studies play a key role in fulfilling the aim of providing patients with an individualised therapy which will reduce risks and improve

Amarante, F., Vilodre, L. C., Maturana, M. A.& Spritzer, P. M. (2011). Women with primary

ovarian insufficiency have lower bone mineral density. *Braz J Med Biol Res,* Vol. 44,

*Liver* **(+) CYP3A5 → VTE Risk x 14,5 (2,8 - 73,9)**

**(-) Expression NRF2 → VTE Risk x 17,9 (3,7 – 85,7)**  J Bouligand et al., Clin Pharm Therap, 2010

M Canonico et al., J Clin Endocrinal Metab, 2008

Phase I Metabolism Cytochrome P450

Oral 17-oestradiol

Metabolites

Phase 2 Metabolism Nrf2 regulated

Detoxification

oestrogens.

**6. Conclusion** 

benefits related to HRT.

No. 1, (Jan 2011), pp. 78-83.

**7. References** 

cardiovascular disease after either oral or transdermal oestrogen administration are also unknown (O'Connell, 1995).

#### **5.3 Venous thromboembolism risk and HRT**

As previously mentioned, VTE represents one of the main adverse effects of HRT in postmenopausal women (Canonico, Plu-Bureau et al., 2008; Cushman et al., 2004). Yet, while oral oestrogen was associated with a significantly increased risk for VTE, this was not observed in women treated with transdermal oestrogen (Canonico et al., 2010; Canonico et al., 2007; Olie et al., 2010; Scarabin et al., 2003; Straczek et al., 2005). An explanation for the distinct VTE risk profile following the two routes of administration involves the first-pass effect of oestrogen. This was shown to affect the synthesis of various oestrogen-dependent hepatic serum factors (Kuhl, 2005), including coagulation and fibrinolysis factors, resulting in blood coagulation activation (Scarabin et al., 1997; Vehkavaara et al., 2001), increased thrombin generation (Scarabin et al., 2011) or induction of resistance to activated protein C (Hemelaar et al., 2006; Oger et al., 2003). However, the precise mechanisms by which these changes occur are still unclear.

#### **5.4 Pharmacogenetics: Genetics factors predisposing to venous thromboembolism (VTE) after oral oestradiol**

Straczek et al. investigated the impact of the route of oestrogen administration on the association between a prothrombotic mutation (factor V Leiden or prothrombin G20210A mutation) and VTE risk. This study confirms the increase risk of VTE due to oral 17βoestradiol in women presenting a genetic predisposition to VTE (Straczek et al., 2005). On the other hand, we have recently suggested that the hepatic metabolism of oestrogen may modulate the risk of VTE either through an increased phase I metabolism or through a decreased phase II metabolism. To address this important question, we have tested genetic polymorphisms capable to modulate oestradiol phase I or phase II liver metabolism. These polymorphisms do not increase the risk of VTE in the absence of HRT. First, we have demonstrated that increased expression of CYP3A5, a phase I enzyme of particular interest in oestrogen liver metabolism, in women carrying the CYP3A5\*1 allele, is associated with a higher risk of VTE during oral oestrogen administration (RR 14.5; CI 2.8 - 73.9), without observing the same interaction in women receiving transdermal oestrogen (Canonico, Bouaziz et al., 2008). Further, we have investigated the association between VTE and nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) polymorphisms (Bouligand et al., 2011). NFE2L2 gene encodes for a transcription factor also known as Nrf2 (NF-E2 related factor 2), essential for both maintenance and induction of phase II metabolism (Thimmulappa et al., 2002). One functional polymorphism (rs6721961) from the promoter region of NFE2L2 was described to be associated with an impaired auto-induction of this transcription factor (Marzec et al., 2007). The presence of this polymorphism may subsequently alter the expression of phase II genes, including those essential for the detoxification of oestrogen metabolites (see Figure 5) (Raftogianis et al., 2000). Our post-hoc analysis of the ESTHER Study (Canonico et al., 2007; Scarabin et al., 2003; Straczek et al., 2005) demonstrated the association between VTE risk and the NFE2L2 polymorphism (i.e. rs672196) in oral oestrogen users (RR 17.9; CI 3.7 – 85.7).

Fig. 5. Genetic polymorphisms modulating liver metabolism and first pass effect of oestrogens.

These pharmacogenetic studies provide new insights suggesting that liver metabolism of oestrogens may be implicated in the pathophysiology of VTE among women using HRT with oral oestrogen therapy. This original finding deserves further investigations in largest and independent series of women receiving oral 17β-oestradiol as well as other oestrogens with different metabolic pathways, not only to treat postmenopausal symptoms but also for contraception. Taking into account the proportion of women using exogenous hormone therapy, these new results may have important clinical implications to improve the stratification of thrombotic risk and identify new groups at high risk.

## **6. Conclusion**

326 Pharmacology

cardiovascular disease after either oral or transdermal oestrogen administration are also

As previously mentioned, VTE represents one of the main adverse effects of HRT in postmenopausal women (Canonico, Plu-Bureau et al., 2008; Cushman et al., 2004). Yet, while oral oestrogen was associated with a significantly increased risk for VTE, this was not observed in women treated with transdermal oestrogen (Canonico et al., 2010; Canonico et al., 2007; Olie et al., 2010; Scarabin et al., 2003; Straczek et al., 2005). An explanation for the distinct VTE risk profile following the two routes of administration involves the first-pass effect of oestrogen. This was shown to affect the synthesis of various oestrogen-dependent hepatic serum factors (Kuhl, 2005), including coagulation and fibrinolysis factors, resulting in blood coagulation activation (Scarabin et al., 1997; Vehkavaara et al., 2001), increased thrombin generation (Scarabin et al., 2011) or induction of resistance to activated protein C (Hemelaar et al., 2006; Oger et al., 2003). However, the precise mechanisms by which these

**5.4 Pharmacogenetics: Genetics factors predisposing to venous thromboembolism** 

Straczek et al. investigated the impact of the route of oestrogen administration on the association between a prothrombotic mutation (factor V Leiden or prothrombin G20210A mutation) and VTE risk. This study confirms the increase risk of VTE due to oral 17βoestradiol in women presenting a genetic predisposition to VTE (Straczek et al., 2005). On the other hand, we have recently suggested that the hepatic metabolism of oestrogen may modulate the risk of VTE either through an increased phase I metabolism or through a decreased phase II metabolism. To address this important question, we have tested genetic polymorphisms capable to modulate oestradiol phase I or phase II liver metabolism. These polymorphisms do not increase the risk of VTE in the absence of HRT. First, we have demonstrated that increased expression of CYP3A5, a phase I enzyme of particular interest in oestrogen liver metabolism, in women carrying the CYP3A5\*1 allele, is associated with a higher risk of VTE during oral oestrogen administration (RR 14.5; CI 2.8 - 73.9), without observing the same interaction in women receiving transdermal oestrogen (Canonico, Bouaziz et al., 2008). Further, we have investigated the association between VTE and nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) polymorphisms (Bouligand et al., 2011). NFE2L2 gene encodes for a transcription factor also known as Nrf2 (NF-E2 related factor 2), essential for both maintenance and induction of phase II metabolism (Thimmulappa et al., 2002). One functional polymorphism (rs6721961) from the promoter region of NFE2L2 was described to be associated with an impaired auto-induction of this transcription factor (Marzec et al., 2007). The presence of this polymorphism may subsequently alter the expression of phase II genes, including those essential for the detoxification of oestrogen metabolites (see Figure 5) (Raftogianis et al., 2000). Our post-hoc analysis of the ESTHER Study (Canonico et al., 2007; Scarabin et al., 2003; Straczek et al., 2005) demonstrated the association between VTE risk and the NFE2L2 polymorphism (i.e. rs672196) in oral

unknown (O'Connell, 1995).

changes occur are still unclear.

**(VTE) after oral oestradiol** 

oestrogen users (RR 17.9; CI 3.7 – 85.7).

**5.3 Venous thromboembolism risk and HRT** 

The increasing life expectancy observed during the last century, without an equivalent change in the average age of menopause, resulted in an increased number of women facing the effects of low ovarian steroids for a longer period of time. Thus, the high interest towards therapeutic options capable to alleviate menopausal symptoms and the extensive research in this field are not surprisingly. Despite the current controversies summarised here which encompass HRT use, further researches will likely improve therapeutic outcomes. In this context, pharmacogenetics studies play a key role in fulfilling the aim of providing patients with an individualised therapy which will reduce risks and improve benefits related to HRT.

#### **7. References**

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**1. Introduction** 

**16** 

*Spain* 

**A Multi-Level Analysis of World** 

and Antonio Perianes-Rodríguez

*Carlos III University of Madrid* 

**Scientific Output in Pharmacology** 

Carlos Olmeda-Gómez, Ma-Antonia Ovalle-Perandones

Over the last few decades and particularly in the present economic context, the distribution of economic resources has been a concern addressed by governmental and corporate scientific policy, which has either benefitted only part of the scientific and technological community or furthered certain lines of research. The pharmaceutical industry in particular has had to confront not only this situation, but also ongoing internationalisation, supported

Until the nineteen eighties, industry internationalisation, in terms of R&D, was a marginal matter, not only for economics theory and business in general, but also for governments and the other organisations involved. Globalisation began to acquire importance after the mid nineteen nineties, although not all manufacturing industries have experienced the same degree of R&D internationalisation. The pharmaceutical industry, for one, pioneered this

Contrary to the widely held opinion according to which R&D internatianlisation is the fruit of domestic innovation in many industries, pharmaceutical constitutes an exception. Indeed, international innovation intensifies the industry's R&D (Patel and Pavitt, 2000), whereas in other lines of business domestic innovation is the driver. In addition to internationalising its R&D, the pharmaceuticals industry has increased its research spending exponentially in

A number of earlier papers studied the bibilometric characteristics of the pharmacological publications generated as a result of the R&D effort in places such as the United States (Narin and Rozek, 1988), India (Kaur and Gupta, 2009; Gupta and Kaur, 2009) or the Middle East (Biglu and Omidi, 2010). Others stressed the contribution of pharmaceutical firms to scientific knowledge (Koening, 1983; McMillan and Hamilton, 2000; Rafols, et al. 2010; Perianes-Rodríguez, et al. 2011). The assessment of the international impact of scientific papers is a present, but not a new concern: it has been a frequent object of study since the nineteen eighties. The use of scientific indicators for several decades to characterise research by subject area, country or institution has confirmed that, although they have their limitations, they are the only suitable tool for scientific assessment (Braun T et al., 1985).

by the relentless advances in communication technologies.

recent years (Congressional Budget Office, 2006).

more universal approach to research and development (Noisi, 1999).

