Endometriose: OP und was dann? Adjuvante Therapiestrategien

Präsentation zum Thema: "Endometriose: OP und was dann? Adjuvante Therapiestrategien"—  Präsentation transkript:

1 Endometriose: OP und was dann? Adjuvante Therapiestrategien
C Tempfer Universitätsklinik für Frauenheilkunde Wien Soma Bay 2010

2 Operative Therapie Fekundität, Fertilität Schmerzen
Cochrane Metaanalyse (Jacobson 2002) lediglich 2 RCTs (Marcoux 1997, Parazzini 1999) 1x negativ, 1x positiv SSR, LGR: OR 1.64 ( ); 10 mos Schmerzen Cochrane Metaanalyse (Jacobson 2001) lediglich 2 RCTs (Sutton 1994, Abbot 2005) Schmerzscore: OR 4.97 ( ) The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

3 ablative OP besser als diagnost. OP (Abbott 2005)
Operative Therapie ablative OP besser als diagnost. OP (Abbott 2005) n= 39; prosp.-rand.; 12 mos; 2nd look 6 mos alle Stadien Schmerzen besser 16/20 (80%) vs. 6/19 (32%) (placebo response!) QOL besser; disease progress. at 2nd look: 45% The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

4 Operative Therapie ablative OP besser als diagnost. OP (Marcoux 1997)
n= 341; prosp.-rand.; resective/ablative vs. diagnostic laparoscopy minimal/mild endometriosis; 36 wks follow-up SS-Rate >20 SSWs besser 50/172 (29%) vs. 29/169 (17%); p=0.006 SS-Inzidenz: 4.7 vs. 2.4 pro 100/mo Morbidität: 3 vs. 1 operative complications The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

5 Exzision – Ablation? Beide Techniken gleich effektiv (Tulandi 1998)
1 RCT: n=24; Wright 2005 kein Unterschied Schmerzscore Retrospektive Daten: n=340; Tulandi 1998 kein Unterschied Schmerzscore, Rezidivrate The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

6 Operative Therapie Zystektomie besser als Fenestrierung
n=100; prosp.-rand.; 2 a (Alborzi 2004) Schmerzrez. 57% vs. 16% Re-OP 23% vs. 6%; SSR 23% vs. 60% n=64; prosp.-rand.; 2 a (Beretta 2002) Dysmenorrhoe 16% vs. 53% Dyspareunie 20% vs. 75% Schmerzrez. 10% vs. 53% RFI 19 mos vs. 10 mos; SSR 67% vs. 24% The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

7 Lipiodol – Sterilität Hum Reprod 2004;19(9):2043-51 Ergebnis
Tubendurchg. per Lipiodol vs. keine Prüfung normale Tuben; infertility n=96 mit Endometriose; n=62 ohne Endometriose Ergebnis bei Pat. mit Endometriose: mehr Schwangerschaften 48% vs. 11% mehr Geburten 40% vs. 11% bei Pat. ohne Endometriose: kein Unterschied The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

8 LUNA - Endometriose Fertil Steril 2003;80(2):310-9
Laparosk. Rand. +/- LUNA n=180; alle Stadien; 3 a Ergebnis Schmerzrezidive gleich 29% vs. 27% (1a) nach 3 a: 36% vs. 32% time to recurrence gleich The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

9 LUNA ohne Endometriose
BJOG 2004;111(9):950-9 Laparosk. Rand. +/- LUNA n=123; CPP; 12mos Ergebnis Schmerzen weniger (-4.8 vs. -0.8) >50% reduction 41% vs. 14% (1a) nur ohne Endometriose The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

10 Prophylakt. Tubektomie
Hum Reprod 2002;17(3):543-8 3 RCTs; sonographically visible hydrosalpinx Meta-analysis Ergebnis pregnancy; OR 1.75 (95% CI ) Birth; OR 2.13 (95% CI ) No difference: miscarriage, complications, ectopic pregnancy The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

11 Optimale Rezidivprophylaxe?
Rezidivraten Hohe Rezidivraten 7–30% nach 3 a 40-50% nach 5 a (Valle 2003) Optimale Rezidivprophylaxe? The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

12 Adjuvante Studien 3mos Hum Reprod 2002;17(4):1128-9 Ergebnis
no adjuvant therapy vs. GnRH-Analogon (Leuprolidazetat 3.75mg) q28x3 n=89; AFS III/IV; 6 mos follow-up Ergebnis Rezidive (Schmerz) gleich 23% vs. 24% objektivierbare Rezidive (Sono, Tastbef.) gleich 9% vs. 9% The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

13 Adjuvante Studien 3mos Hum Reprod 1999;14(5):1335-7 Ergebnis
no adjuvant therapy vs. danazol 600mg/d for 3 mos n=77; AFS III/IV; 12 mos follow-up Ergebnis Rezidive (Schmerz) gleich 7/31 (23%) vs. 9/29 (31%); p=n.s. objektivierbare Rezidive (Sono, Tastbef.) gleich 8% vs. 15% SS-Raten gleich 6/11 vs. 8/16 The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

14 Goserelin Br J Obstet Gynaecol 1999;106(7):672-7 Ergebnis
no therapy vs. goserelin (Zoladex®) s.c. q28x6 n=269; AFS II bis IV; 24 mos Ergebnis weniger Rezidive n. 1a: 13% vs. 21% weniger Rezidive n. 2a: 23% vs. 36% rezidivfreies Intervall sign. länger The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

15 GnRH + Anastrozol Hum Reprod 2004;19(1):160-7 Ergebnis
OP + Goserelin 3.6mg q28x6 +/- Anastrozol 1mg/d 6 mos n=97; severe endometriosis (rASRM score >40); 24 mos follow-up Ergebnis länger rez.-frei 2.4 vs. 1.7 mos (p=0.009) weniger Schmerzrezidive 35% vs. 8% BMD-Verlust höher; QOL gleich The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

16 Low-Dose sDanazol Hum Reprod 1999;14(9):2371-4 Ergebnis
alle: surgery + GnRH-Analogon (triptorelin 3.75mg) q28x6, dann: rand.: danazol 100mg/d f. 6 mos vs. no further therapy n=28; AFS III/IV; 24 mos follow-up Ergebnis Schmerzscore besser p<0.01 Rezidive 44 vs. 67% p<0.05 side effects gleich The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

17 Mirena® post OP Schmerzrezidive seltener
Fertil Steril 2003;80(2):305-9 n= 40; randomisiert; surgery +/- IUD alle Stadien; 12 mos follow-up Ergebnis Schmerzrezidive seltener 2/20 (10%) vs. 9/20 (45%) höhere Zufriedenheit 15/20 (75%) vs. 10/20 (50%) A range of systemic drugs can be delivered intranasaly, which is more comfortable and convenient than the parenteral route. Some drugs such as demopressin are delivered sucessfully via the intranasal route, whereas others such as insulin are not. Pharmacologically active polypeptides such as hormones and vaccines avoid both the hepatic first pass effect and metabolism by enzymes in the gut lumen or wall. The nasal route is potentially important for the long term administration of proteins or peptides. The long term compliance of patients taking systemeic drugs delivered intranasally is good. At present several systemic drugs are licensed for transnasal delivery : Desmopressin : Diabetes insipidus LHRH : contraceptive agents assessing the reserve of luteinising hormones and follicle-stimulating hormones from the pituitary gland may have a role in the differential diagnosis of hypogonadism and delayed puberty. Synthetic salmon calcitonin : osteoporosis (Hong Kong) COMPLIANCE: Hirvonene Br J Obstet Gynaecol

18 Mirena® Hum Reprod; E-publ. March 24, 2005
n= 82; Endometriose + CPP/Dysmenorrhoe LNG-IUD vs. GnRH-Analogon (Lupron dep. 3.75mg q28 x 6) Ergebnis gleich effektiv CPP kein Unterschied (p=0.9) 1. Monat blutungsfrei 34% vs. 71% 6. Monat blutungsfrei 70% vs. 98% A range of systemic drugs can be delivered intranasaly, which is more comfortable and convenient than the parenteral route. Some drugs such as demopressin are delivered sucessfully via the intranasal route, whereas others such as insulin are not. Pharmacologically active polypeptides such as hormones and vaccines avoid both the hepatic first pass effect and metabolism by enzymes in the gut lumen or wall. The nasal route is potentially important for the long term administration of proteins or peptides. The long term compliance of patients taking systemeic drugs delivered intranasally is good. At present several systemic drugs are licensed for transnasal delivery : Desmopressin : Diabetes insipidus LHRH : contraceptive agents assessing the reserve of luteinising hormones and follicle-stimulating hormones from the pituitary gland may have a role in the differential diagnosis of hypogonadism and delayed puberty. Synthetic salmon calcitonin : osteoporosis (Hong Kong) COMPLIANCE: Hirvonene Br J Obstet Gynaecol

19 Endometriose – IVF/ICSI
Adjuvante Therapie besser vor ART? 3 RCTs (Rickes 2002; Tsai 2004; Surrey 2002) n=51, 110, 63 3/6 mo GnRH-Analoga vs. no therapy/Danazol Fekundität besser (84% vs. 54%) pregnancy rate besser höhere Rate an Oozyten The nasal route of administration The nasal route represents a highly effective means of drug delivery. Intranasal drug absorption is facilitated by the highly vascularized, microvillous nature of the nasal mucosa, which provides an absorption surface estimated at 160 cm2. Each cell has about cilia and there are microvilli between the cilia which greatly increase the surface for absorption. They are covered by an hydrophilic mucus whose outer layer is relatively viscous and moves over the surface of the cilia. This mucus will trap dust and bacteria. The cilia beat with a powerful forward stroke and this rhythmic activity is responsible for the mucociliary clearance. Any drug deposited locally is therefore moved posteriorly, this antero-posterior transit time allowing local absorption, the non absorbed fraction being swallowed. Beneath the mucosa lies a complex vascular system including erectile tissue composed of sinusoids under autonomic nervous control which rapidly convey any substances absorbed across the epithelium into the systemic blood stream. Thus the absorption of drugs via a nasal route may be dependent upon the patency of the nasal airway, the retention of the drug on the mucosal surface, the mucociliary clearance function and the vascularity of the nasal mucosa. Hydrophilic substances dissolve rapidly and diffuse to the highly vascular cell lining from where they are absorbed into the general circulation. The bioavailability of a drug is also affected by factors related to the drug itself, such as molecular size and lipophilicity, and those related to the drug vehicle. Preliminary clinical experiences have documented that this route is appropriate for estrogen. The lining of the nasal cavity, showing little in the way of enzymatic function, is particularly well adapted to the absorption of products, such as estradiol, which are subjected to considerable intestinal metabolism when given orally. The nasal route is already being used with success for certain other long-term therapies eg, LHRH agonists and calcitonin. Other drugs such as insulin, vaccines, and nicotine compounds are currently under development for intranasal use.

20 OC post OP A range of systemic drugs can be delivered intranasaly, which is more comfortable and convenient than the parenteral route. Some drugs such as demopressin are delivered sucessfully via the intranasal route, whereas others such as insulin are not. Pharmacologically active polypeptides such as hormones and vaccines avoid both the hepatic first pass effect and metabolism by enzymes in the gut lumen or wall. The nasal route is potentially important for the long term administration of proteins or peptides. The long term compliance of patients taking systemeic drugs delivered intranasally is good. At present several systemic drugs are licensed for transnasal delivery : Desmopressin : Diabetes insipidus LHRH : contraceptive agents assessing the reserve of luteinising hormones and follicle-stimulating hormones from the pituitary gland may have a role in the differential diagnosis of hypogonadism and delayed puberty. Synthetic salmon calcitonin : osteoporosis (Hong Kong) COMPLIANCE: Hirvonene Br J Obstet Gynaecol

21 OC post OP Schmerzrezidive seltener, wenn >1 a 7 Studien; 4 RCTs
Kombinationspillen nach OP Ergebnis Schmerzrezidive seltener, wenn >1 a Frequenz, Intensität anatomische Rezidive seltener kontinuierlich-zyklisch gleich effektiv A range of systemic drugs can be delivered intranasaly, which is more comfortable and convenient than the parenteral route. Some drugs such as demopressin are delivered sucessfully via the intranasal route, whereas others such as insulin are not. Pharmacologically active polypeptides such as hormones and vaccines avoid both the hepatic first pass effect and metabolism by enzymes in the gut lumen or wall. The nasal route is potentially important for the long term administration of proteins or peptides. The long term compliance of patients taking systemeic drugs delivered intranasally is good. At present several systemic drugs are licensed for transnasal delivery : Desmopressin : Diabetes insipidus LHRH : contraceptive agents assessing the reserve of luteinising hormones and follicle-stimulating hormones from the pituitary gland may have a role in the differential diagnosis of hypogonadism and delayed puberty. Synthetic salmon calcitonin : osteoporosis (Hong Kong) COMPLIANCE: Hirvonene Br J Obstet Gynaecol

22 Dydrogesteron Schmerzrezidive seltener
Overton et al. Fertil Steril 1994 n=62; RCT; minimal/mild; surgery + Dydrogesteron 40 or 60mg/d d16-28 q6 or placebo 12 mos follow-up Ergebnis Schmerzrezidive seltener Effekt bis 12 mos nachweisbar A range of systemic drugs can be delivered intranasaly, which is more comfortable and convenient than the parenteral route. Some drugs such as demopressin are delivered sucessfully via the intranasal route, whereas others such as insulin are not. Pharmacologically active polypeptides such as hormones and vaccines avoid both the hepatic first pass effect and metabolism by enzymes in the gut lumen or wall. The nasal route is potentially important for the long term administration of proteins or peptides. The long term compliance of patients taking systemeic drugs delivered intranasally is good. At present several systemic drugs are licensed for transnasal delivery : Desmopressin : Diabetes insipidus LHRH : contraceptive agents assessing the reserve of luteinising hormones and follicle-stimulating hormones from the pituitary gland may have a role in the differential diagnosis of hypogonadism and delayed puberty. Synthetic salmon calcitonin : osteoporosis (Hong Kong) COMPLIANCE: Hirvonene Br J Obstet Gynaecol

23 Dydrogesteron Trivedi et al. Gynecol Endocrinol 2007
n=98; alle Stadien; prosp., offen; surgery + Dydrogesteron 10-20mg/d d5-25 q3-6 Ergebnis Dyspareunie, Dysmenorrhoe reduziert nach 1. Zyklus (jeweils p<0.05) Menses: Dauer + Intensität reduziert (p<0.05) hohe Zufriedenheit (74%) A range of systemic drugs can be delivered intranasaly, which is more comfortable and convenient than the parenteral route. Some drugs such as demopressin are delivered sucessfully via the intranasal route, whereas others such as insulin are not. Pharmacologically active polypeptides such as hormones and vaccines avoid both the hepatic first pass effect and metabolism by enzymes in the gut lumen or wall. The nasal route is potentially important for the long term administration of proteins or peptides. The long term compliance of patients taking systemeic drugs delivered intranasally is good. At present several systemic drugs are licensed for transnasal delivery : Desmopressin : Diabetes insipidus LHRH : contraceptive agents assessing the reserve of luteinising hormones and follicle-stimulating hormones from the pituitary gland may have a role in the differential diagnosis of hypogonadism and delayed puberty. Synthetic salmon calcitonin : osteoporosis (Hong Kong) COMPLIANCE: Hirvonene Br J Obstet Gynaecol

24 MPA n=274; 50 PrüZ CAN/USA; Endometriose; RCT
104 mg MPA s.c. vs mg Leuprolinazetat i.m. 2 x 3 mos + 12 mos follow-up Outcome: Dysmenorrhoe, Dyspareunie, UB-Schmerzen Knochendichte MPA gleich effektiv, weniger BMD-Verlust, weniger hypoöstrogene Beschw., mehr Blutungen A range of systemic drugs can be delivered intranasaly, which is more comfortable and convenient than the parenteral route. Some drugs such as demopressin are delivered sucessfully via the intranasal route, whereas others such as insulin are not. Pharmacologically active polypeptides such as hormones and vaccines avoid both the hepatic first pass effect and metabolism by enzymes in the gut lumen or wall. The nasal route is potentially important for the long term administration of proteins or peptides. The long term compliance of patients taking systemeic drugs delivered intranasally is good. At present several systemic drugs are licensed for transnasal delivery : Desmopressin : Diabetes insipidus LHRH : contraceptive agents assessing the reserve of luteinising hormones and follicle-stimulating hormones from the pituitary gland may have a role in the differential diagnosis of hypogonadism and delayed puberty. Synthetic salmon calcitonin : osteoporosis (Hong Kong) COMPLIANCE: Hirvonene Br J Obstet Gynaecol

25 MPA (A) Results for patients in the DMPA-SC 104 group.
(B) Results for patients in the leuprolide group. A range of systemic drugs can be delivered intranasaly, which is more comfortable and convenient than the parenteral route. Some drugs such as demopressin are delivered sucessfully via the intranasal route, whereas others such as insulin are not. Pharmacologically active polypeptides such as hormones and vaccines avoid both the hepatic first pass effect and metabolism by enzymes in the gut lumen or wall. The nasal route is potentially important for the long term administration of proteins or peptides. The long term compliance of patients taking systemeic drugs delivered intranasally is good. At present several systemic drugs are licensed for transnasal delivery : Desmopressin : Diabetes insipidus LHRH : contraceptive agents assessing the reserve of luteinising hormones and follicle-stimulating hormones from the pituitary gland may have a role in the differential diagnosis of hypogonadism and delayed puberty. Synthetic salmon calcitonin : osteoporosis (Hong Kong) COMPLIANCE: Hirvonene Br J Obstet Gynaecol

26 MPA (A) Results for patients in the DMPA-SC 104 group.
(B) Results for patients in the leuprolide group. A range of systemic drugs can be delivered intranasaly, which is more comfortable and convenient than the parenteral route. Some drugs such as demopressin are delivered sucessfully via the intranasal route, whereas others such as insulin are not. Pharmacologically active polypeptides such as hormones and vaccines avoid both the hepatic first pass effect and metabolism by enzymes in the gut lumen or wall. The nasal route is potentially important for the long term administration of proteins or peptides. The long term compliance of patients taking systemeic drugs delivered intranasally is good. At present several systemic drugs are licensed for transnasal delivery : Desmopressin : Diabetes insipidus LHRH : contraceptive agents assessing the reserve of luteinising hormones and follicle-stimulating hormones from the pituitary gland may have a role in the differential diagnosis of hypogonadism and delayed puberty. Synthetic salmon calcitonin : osteoporosis (Hong Kong) COMPLIANCE: Hirvonene Br J Obstet Gynaecol

27 MPA MPA sc signifikante Verbesserung vs baseline:
hours of employment lost/mo 1.14 vs (p<0.05) hours of productivity lost at employment/mo 10.45 vs (p<0.05) hours of housework lost/mo 3.64 vs (p<0.05) A range of systemic drugs can be delivered intranasaly, which is more comfortable and convenient than the parenteral route. Some drugs such as demopressin are delivered sucessfully via the intranasal route, whereas others such as insulin are not. Pharmacologically active polypeptides such as hormones and vaccines avoid both the hepatic first pass effect and metabolism by enzymes in the gut lumen or wall. The nasal route is potentially important for the long term administration of proteins or peptides. The long term compliance of patients taking systemeic drugs delivered intranasally is good. At present several systemic drugs are licensed for transnasal delivery : Desmopressin : Diabetes insipidus LHRH : contraceptive agents assessing the reserve of luteinising hormones and follicle-stimulating hormones from the pituitary gland may have a role in the differential diagnosis of hypogonadism and delayed puberty. Synthetic salmon calcitonin : osteoporosis (Hong Kong) COMPLIANCE: Hirvonene Br J Obstet Gynaecol

28 Adjuvante Therapie Empfehlungen der Klin. Abt. f. Gynäkologische Endokrinologie und Sterilitätsbehandlung der Universitätsfrauenklinik Wien zur adjuvanten Behandlung von Frauen mit histologisch gesicherter, symptomatischer Endometriose ohne aktuellen Kinderwunsch 1. Triptorelinazetat 4.12mg (Decapeptyl® Depot) i.m. q28x6 + Danazol 100mg/d f. 6 Mo + add back-Therapie bei klimakterischem Syndrom (z.B. Femoston conti [2mg E2-Hemihydrat/10mg Dydrogesteron] Tbl. 1x1 tgl.) - Osteodensitometrie n. 6 Mo Lit.: Hum Reprod 1999;14(9):2371-4: Schmerzkontrolle mit Danazol signifikant besser vs. ohne Danazol 2. GnRH-Analoga: Goserelinazetat 3.6mg (Zoladex®), Leuprolinazetat 3.75mg (Enantone-GYN®), Triptorelinazetat 4.12mg (Decapeptyl Depot®) q28x6 + add back-Therapie bei klimakterischem Syndrom - Osteodensitometrie n. 6 Mo Lit.: Br J Obstet Gynaecol 1999;106(7):672-7: sign. längeres rezidivfreies Intervall für Goserelinazetat 3. Goserelinazetat 3.6mg (Zoladex®) s.c. q28x6 + Anastrozol 1mg/d (Arimidex®) f. 6 Mo + add back-Therapie bei klimakterischem Syndrom - Osteodensitometrie n. 6 Mo Lit.: Hum Reprod 2004;19(1):160-7: sign. weniger Rezidive n. 24 Mo (35% vs. 8%); sign. läng. rezidivfr. Intervall (1.7 Mo vs. 2.4 Mo); cave: Arimidex chefarztpflichtig + off label use 4. Levonorgestrelpessar (Mirena®) Lit.: Fertil Steril 2003;80(2):305-9: sign. weniger Schmerzrezidive n. 12 Mo (10% vs. 45%); sign. höhere Zufriedenheit (75% vs. 50%) 5. Orales Kontrazeptivum Lit.: keine; Empfehlung long cycle (Einnanhme 1x1 Drg. f. 3 Monate, dann 1 Woche Pause) 6. Etonogestrelimplantat (Implanon®) Lit.: eigene Daten bei Rezidivtherapie (Wenzl et al., submitted) Empfehlung für Frau Klebeetikette Datum: Decapeptyl® Depot i.m. q28x6 + Danazol 100mg/d f. 6 Mo +/- Femoston conti Tbl. 1x1 tgl. GnRH-Analogon q28x6 +/- Femoston conti Tbl. 1x1 tgl. Zoladex® 3.6mg s.c. q28x6 + Arimidex® 1mg/d f. 6 Mo +/- Femoston conti Tbl. 1x1 tgl. Mirena® Implanon® Orales Kontrazeptivum - Präparat: __________________ A range of systemic drugs can be delivered intranasaly, which is more comfortable and convenient than the parenteral route. Some drugs such as demopressin are delivered sucessfully via the intranasal route, whereas others such as insulin are not. Pharmacologically active polypeptides such as hormones and vaccines avoid both the hepatic first pass effect and metabolism by enzymes in the gut lumen or wall. The nasal route is potentially important for the long term administration of proteins or peptides. The long term compliance of patients taking systemeic drugs delivered intranasally is good. At present several systemic drugs are licensed for transnasal delivery : Desmopressin : Diabetes insipidus LHRH : contraceptive agents assessing the reserve of luteinising hormones and follicle-stimulating hormones from the pituitary gland may have a role in the differential diagnosis of hypogonadism and delayed puberty. Synthetic salmon calcitonin : osteoporosis (Hong Kong) COMPLIANCE: Hirvonene Br J Obstet Gynaecol

29 Zusammenfassung Operative Therapie: schmale Datengrundlage
Schmerzen, Fertilität ablativ, destruktiv, Zystektomie Adjuvant: 3 mos kein Effekt – 6 mos GnRH q28x6 GnRH q28x6 + Anastrozol 1mg f. 6 mos GnRH q28x6; sequ. low-dose Danazol f. 6 mos Gestagene LNG-IUD post OP OC f. 1 a Dydrogesteron A range of systemic drugs can be delivered intranasaly, which is more comfortable and convenient than the parenteral route. Some drugs such as demopressin are delivered sucessfully via the intranasal route, whereas others such as insulin are not. Pharmacologically active polypeptides such as hormones and vaccines avoid both the hepatic first pass effect and metabolism by enzymes in the gut lumen or wall. The nasal route is potentially important for the long term administration of proteins or peptides. The long term compliance of patients taking systemeic drugs delivered intranasally is good. At present several systemic drugs are licensed for transnasal delivery : Desmopressin : Diabetes insipidus LHRH : contraceptive agents assessing the reserve of luteinising hormones and follicle-stimulating hormones from the pituitary gland may have a role in the differential diagnosis of hypogonadism and delayed puberty. Synthetic salmon calcitonin : osteoporosis (Hong Kong) COMPLIANCE: Hirvonene Br J Obstet Gynaecol