Hormonal treatment throughout a woman´s life: contraception, pro-fertility and menopause

Ingrid J M Duijkers^†

Dinox Medical Investigations, 6524 TX Nijmegen, The Netherlands

author email† Presenting author

2002 Joint Annual Meeting of the Arbeitsgemeinschaft für Angewandte Humanpharmakologie (Association for Applied Human Pharmacology) and the American College of Clinical Pharmacology
Garmisch-Partenkirchen, Germany, 27-29 January 2002

AGAH 2002, 1:op010

Received:	25 March 2002
Published:	4 April 2002

Background

Many women use hormonal drugs. These drugs are taken to prevent a pregnancy, to become pregnant, or to substitute the loss of endogenous hormones after meno-pause. Gynaecological endocrinology is a special field within clinical pharmacology because of the extensive use of drugs by a healthy population. Particular characteristics of the population and design of clinical studies with hormonal drugs will be discussed.

Hormonal contraception

Although hormonal contraceptives may be used for the treatment of diseases (acne or certain gynaecological disorders), the most important application is the prevention of pregnancies in healthy women. Preparations contain a combination of an oestrogen and a progestogen or only a progestogen, and various routes of ad-ministra-tion are applied. From phase I in clinical development onwards the study population is similar to the target population, namely healthy women of reproductive age. In an early stage of the development of a new preparation the efficacy is in-vestiga-ted by ovulation inhibition studies, using transvaginal ultrasonography and hormone determinations. When a preparation does not consistently inhibit ovulation, endometrial histology and cervical mucus quality will be investigated. In a later stage of development the pregnancy rate is assessed by calculation of the Pearl Index and by life table analysis. Assessment of the pregnancy rate requires a large number of study cycles. Metabolic effects will also be investigated, in particular the effects on other endocrine parameters, on haemostasis, carbohydrate and lipid metabolism, and in the case of progestogen-only preparations, on bone mineral density.

An important tolerability aspect of a new preparation is the degree of cycle control. Safety parameters include the follow-up of pregnancies and the return of fertility. A difficulty in the design of studies with hormonal contraceptives is the menstrual cycle dependency of the treatment.

Profertility therapy

Profertility drugs are used to treat subfertile women or fertile women with subfertile partners. These preparations stimulate pituitary or ovarian function. They may be used in combination with preparations which suppress pituitary function, thus preventing premature ovulation and treatment cycle cancellation. Early studies with profertility drugs may be performed in postmenopausal volunteers or female volunteers of reproductive age, but also in hypogonadotrophic hypogonadal subjects in order to prevent the interference of endogenous hormones. In later stages studies are performed in patients undergoing infertility treatment. The efficacy of drugs stimulating pituitary or ovarian function is studied by ultrasound assessment of follicular growth, measurement of hormonal parameters, and determination of ovulation and pregnancy rates. These studies are either performed in spontaneous menstrual cycles or during suppression of endogenous hormones by a high-dose oral contraceptive or a gonadotrophin-releasing hormone analogue. The efficacy of drugs suppressing pituitary function can be studied in spontaneous menstrual cycles by ultrasonography and hormone determinations. The efficacy of these drugs in ovarian stimulation cycles is investigated by assessment of the cancellation and pregnancy rates. Safety parameters include the follow-up of pregnancies and children. Also profertility drug studies may have a complicated design because of cycle dependency of the treatment.

Hormonal replacement therapy

Hormonal replacement therapy is used by peri- and postmenopausal women to prevent or treat osteoporosis or to reduce climacteric symptoms. Preparations contain either an oestrogen, a combination of an oestrogen and a progestogen, tibolon or a selective oestrogen receptor modulator. In all phases of clinical drug development the study population comprises healthy peri- or postmenopausal volunteers with or without climacteric complaints, which is also the target population. In early stages of development of a preparation the efficacy in the prevention and treatment of osteoporosis may be studied by biochemical markers and bone densitometry. In a later stage the primary endpoint, the number of bone fractures, is assessed, requiring large and long-lasting studies. The efficacy in the reduction of climacteric complaints is investigated by registration of the number of hot flushes by the subject and by calculation of the Kupperman Index. Safety and tolerability parameters include the vaginal bleeding pattern, endometrial histology, effects on haemostasis, carbohydrate and lipid metabolism, and mammography.

Summary