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WO1999066935A1 - Contraceptif masculin renfermant un inhibiteur de la prolactine et un steroide sexuel - Google Patents

Contraceptif masculin renfermant un inhibiteur de la prolactine et un steroide sexuel Download PDF

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Publication number
WO1999066935A1
WO1999066935A1 PCT/GB1999/001948 GB9901948W WO9966935A1 WO 1999066935 A1 WO1999066935 A1 WO 1999066935A1 GB 9901948 W GB9901948 W GB 9901948W WO 9966935 A1 WO9966935 A1 WO 9966935A1
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WIPO (PCT)
Prior art keywords
prolactin
sex steroid
testosterone
kit
inhibitor
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/GB1999/001948
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English (en)
Inventor
Gerald Anthony Lincoln
Frederick Wu
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Medical Research Council
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Medical Research Council
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Filing date
Publication date
Application filed by Medical Research Council filed Critical Medical Research Council
Priority to AU43825/99A priority Critical patent/AU4382599A/en
Publication of WO1999066935A1 publication Critical patent/WO1999066935A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol

Definitions

  • the present invention relates to a reversible male contraceptive, based upon a combination of a prolactin inhibitor and a sex steroid/androgen.
  • the pituitary produced lactogenic hormone prolactin (also known as luteotrophin) is known to be one of the major hormones affecting male reproductive function. Whilst the gonadotrophins luteinizing hormone (LH) and follicle stimulating hormone (FSH) both stimulate spermatogenesis, it is generally accepted that elevated prolactin is inhibitory to normal reproductive function in both men and women (see Huhtaniemi et al . , "Combination of a GnRH agonist with an antiandrogen or bromocriptine in the treatment of prostatic cancer; slight potentiation of an igonal effects", Int. J. of Andrology 14:374-386, 1991).
  • LH gonadotrophins luteinizing hormone
  • FSH follicle stimulating hormone
  • prolactin inhibitor eg NORPROLAC (TM) of Sandoz Pharmaceuticals
  • prolactin hyperprolactinemia
  • hypoprolactinemia hypoprolactinemia
  • Orisakwe reported (in their article entitled “Restoration of normal sperm characteristics in hypoprolactineamic infertile men treated with metoclopromide and exogenous prolactin” , Clinical Pharmacology and Therapeutics 58: 354-359, 1995) that administration of exogenous- prolactin to these patients readily restored normal sperm characteristics.
  • the present invention provides a male contraceptive, said contraceptive comprising: i) a prolactin inhibitor; and ii) a sex steroid.
  • the prolactin inhibitor will preferably inhibit prolactin secretion, but may alternatively operate by preventing the activity of prolactin in the testis.
  • a suitable prolactin inhibitor is quinagolide, sold under the trade name NORPROLAC (TM) of Sandoz Pharmaceuticals, but other Dopamine D2 receptor agonists are also acceptable.
  • Commercially available agonists include Bromocriptine and Cabergoline.
  • the sex steroid which is preferably a male sex steroid or androgen, will inhibit gonadotrophin secretion whilst enabling normal male behaviour to be maintained.
  • Any sex steroid hormone which reduces gonadotrophin secretion will be suitable and the term "sex steroid" as used herein encompasses not only naturally occurring sex steroid compounds (such as testosterone) , but includes also precursors therefor (eg. androstenedione) , but also synthetic analogues thereof which may be especially desirable for oral administration. Testosterone esters are especially suitable.
  • the sex steroid may be administered by injection, as a transdermal patch, as a sub-cutaneous implant or orally, for example by capsule.
  • testosterone implant an acceptable dosage for a period 4 months can be sustained.
  • suitable compositions are available commercially for injection or for implant administration.
  • suitable testosterone esters include testosterone enanthanate, testosterone propionate, testosterone phenylpropionate, testosterone isocaproate, testosterone decanoate or the like.
  • the prolactin inhibitor and sex steroid may be administered by the same or different routes and at the same or different times.
  • a composition comprising both active ingredients in admixture is convenient, especially when adapted for oral administration, this is by no means essential for the present invention which merely requires that levels of sex steroid are elevated whilst endogenous levels of prolactin are suppressed or prolactin activity otherwise reduced.
  • sequential administration of the two active ingredients may be preferred:
  • the present invention thus also provides a kit for male contraception comprising i) a prolactin inhibitor, and packaged separately thereto ii) a sex steroid.
  • Administration of the sex steroid (androgen) suppresses production of the classical gonadotrophins (LH and FSH) and administration of the prolactin inhibitor either suppresses the secretion of prolactin and hence the action of prolactin at the testis or reduces the activity of prolactin in the testis.
  • LH and FSH classical gonadotrophins
  • prolactin inhibitor and testosterone (or equivalent) as a male contraceptive has the following potential advantages:
  • Prolactin normally acts in the testis synergistically with LH and FSH to maintain both steroidogenesis and spermatogenesis, thus lowering prolactin will reduce these effects.
  • the present invention provides a method of inducing azoospermia in mammalian males (preferably human males) , said method comprising: a) administering an effective dose of a prolactin inhibitor; and b) administering an effective dose of a sex steroid.
  • the sex steroid may be administered by subcutaneous implant (usually an implant 400 to 1500 mg, preferably 600 to 1200 mg of sex steroid) which provides an effective dose over a sustained period eg 4 months or longer.
  • the sex steroid may be administered by injection and a single weekly dose of between 50 mg to 300 mg, preferably 150 to 200 mg, should be suitable.
  • An example of a commercially available formulation for injection is SUSTANON 250 (TM) of Organon Laboratories Ltd.
  • a daily dose of testosterone may also be taken for example orally in tablet or capsule form and a dose of 5 to 40 mg may be suitable.
  • the prolactin inhibitor is preferably a non-ergot D2 receptor agonist, such as quinagolide (NORPROLAC) .
  • the prolactin inhibitor may be taken daily, by the oral route, at a suitable dose.
  • a suitable daily dose may be 25 ⁇ g/day to 200 ⁇ g/day, preferably 50 ⁇ g/day to 150 ⁇ g/day, for example 60 ⁇ g/day to 100 ⁇ g/day. 75 ⁇ g/day should be suitable. It could also be administered as a long-acting injection or implant.
  • the present invention provides the use of a prolactin inhibitor in the manufacture of a medicament which in combination with exogenously administered sex steroid is effective in treating fertile males to reduce their fertility.
  • the present invention provides the use of exogenous sex steroid in the manufacture of a medicament which in conjunction with exogenously administered prolactin inhibitor is effective in treating fertile males to reduce their fertility.
  • FIG 1 shows schematically the experimental protocol followed in the example.
  • Prolactin inhibition will be achieved by the daily treatment with an orally active, non-ergot, dopamme D2 receptor agonist, Quinagolide (Norprolac : Sandoz Pharmaceuticals) and gonadotrophin inhibition will be induced by the simultaneous administration of subcutaneous testosterone implants (Organon Laboratories) .
  • Testosterone implant only high T control
  • Testosterone implant (high T) plus Norprolac (NOR) administered for 24 weeks high T+NOR
  • Testosterone implant (low T) plus Norprolac for 24 weeks low T+NOR part
  • the study will extend over a total of 9 months defined as 1 month pre - treatment , 4 months treatment and 4 months recovery (see Figure 1) .
  • the protocol is designed to establish whether prolactin inhibition combined with exogenous testosterone produces a more rapid and complete induction of azoospermia compared to testosterone alone, and whether prolactin inhibition delays the recovery of normal testicular function after withdrawal of testosterone.
  • Each subject will be studied in four phases : -
  • Two fasting blood samples will be collected for routine haematology (haemoglobin, haematocrit and white cell count) and biochemistry - electrolytes, urea, creatinine, liver function tests (albumin, AST, ALT, GGT, alkaline phosphatase) , glucose, lipids (total cholesterol, LDL and HDL cholesterol) and baseline hormone analyses (LH, FSH, testosterone) .
  • haematology haemoglobin, haematocrit and white cell count
  • biochemistry - electrolytes urea
  • creatinine creatinine
  • liver function tests albumin, AST, ALT, GGT, alkaline phosphatase
  • glucose total cholesterol, LDL and HDL cholesterol
  • baseline hormone analyses LH, FSH, testosterone
  • Treatment phase (16 weeks) Subjects will only commence this phase when all parameters in the previous 4 weeks are confirmed to be normal.
  • the treatment phase is initiated at testosterone implant with or without starting Norprolac simultaneously.
  • Each subject will have a medical review, physical examination, blood and semen analyses at 4 weekly intervals. Diaries/questionnaires will be completed weekly.
  • Recovery phase (approx 16 weeks) All subjects will be followed until they attain the recovery criteria. Recovery is defined as (a) when the geometric mean pre-treatment sperm density is reached or (b) 3 consecutive specimens show sperm density>20 million/ml. Medical review, physical examination, semen analyses and blood sampling will be carried out at 4 weekly intervals until the recovery phase terminates. Diaries/questionnaires will be completed weekly.
  • Subjects Healthy adult men from the general community will be recruited into the three study groups each comprising 16 subjects making a total of 48.
  • Subj ect exclusion cri teria Past or present disturbance of liver function - Hyperlipoproteinaemia - Diabetes mellitus or carbohydrate intolerance - Cardiac diseases - Hypertension (Diastolic >90 mm/Hg) - Prostatic disease - Genitourinary infection - Psychiatric illness - Alcohol abuse - Drug abuse - Use of one or more of the following medications: sex steroids, hydantoins, barbiturates, primidone, carbemazapine, rifampicin, griseofulvin.
  • Norprolac Norprolac will be administered as a daily oral tablet taken at bedtime (75 ⁇ g/day, Norprolac, Sandoz; Product Licence No . PL0101/0382) .
  • This treatment has been found to effectively suppress prolactin secretion in patients with hyperprolactinemia and is well tolerated (Brownell et al . , "The treatment of hyperprolactinemia from bromocriptine to Norprolac", In Norprolac (quinagolide) : an update. Ed J. Brownell pp 7-11, Medical Forum Int. The Netherlands, 1996).
  • Testosterone will be administered using slow-release, release subcutaneous testosterone implants given on one occasion at the start of the study (4x200mg or 6x200mg testosterone, Testosterone implant, Organon Laboratories Ltd; Product Licence No. 0065/5084R) .
  • Testosterone implants have been used for over 30 years in clinical practice as a standard form of androgen substitution for treatment of male hypogonadism. It is remarkably free from side-effects. Extrusion of pellets, and local infection occurs in less than 5% of cases but are seldom a problem in experienced hands.
  • the dose (800 mg or 1200mg) used in this study is higher than the standard replacement of dose of 600-800 mg .
  • testosterone implant in doses up to 1200mg has been shown to cause no side effects for up to 6 months (Handelsman et al . , "Establishing the minimum effective dose and additive effects of depot progestin in suppression of human spermatogenesis by a testosterone depot", Journal of Clinical Endocrinology and Metabolism 81: 4113-4121, 1996). Weight-gain, acne and changes in behaviour and lipoproteins are possible undesirable effects of higher doses of testosterone compared to that used in this study.
  • Testosterone implant The implant procedure is carried out by aseptic technique under local lignocaine anaesthesia through a 1 - 2 cm surgical incision of the anterior abdominal wall. A metal trocar and cannula are used to introduce the four or six testosterone pellets into the subcutaneous fatty tissue. The incision is closed by non-absorbable sutures (2-0 black silk) which are removed after 4 days. The discomfort of the implant procedure is minimal and well -tolerated.
  • Venepuncture Venous blood will be obtained from an arm vein by venepuncture through a 21G needle. Between 20 -30ml of blood is collected on each occasion. Semen collection Ejaculated semen is collected by masturbation after a period of abstinence of 2-5 days, The sample can be produced in the Subfertility Laboratory Donor Rooms or at home within 60 minutes of analysis.
  • hormonal parameters LH, FSH, prolactin, testosterone, dihydrotestosterone, oestradiol, sex- hormone binding globulin
  • Testosterone has been used by the WHO Task Force on Male Fertility Regulation in clinical trials involving over 700 healthy men. In these studies, supraphysiological doses of testosterone had been delivered by weekly injections of testosterone enanthate. In this study, testosterone is delivered by a single administration of testosterone pellet implants which not only contain a lower total dose but produce stable rather than fluctuating levels of testosterone compared to weekly injections. Testosterone implants have been used for over 30 years in clinical practice as a standard form of androgen substitution for treatment of male hypogonadism. It is remarkably free from side-effects. Extrusion of pellets, and local infection occurs in less than 5% of cases but are seldom a problem in experienced hands. The implant procedure carried out under local anaesthesia is well- tolerated.
  • Quinalgolide is an approved oral dopamine agonist for the treatment of hyperprolactinaemia . Its main indication is in patients who are unable to tolerate the side effects of the more established drug, Bromocriptine. Norprolac is believed to produce less side effects because it is, unlike its predecessors, a (the first to be marketed) non-ergot dopamine agonist .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention a trait à un contraceptif masculin comportant comme ingrédients actifs un inhibiteur de la prolactine et un stéroïde sexuel ou un androgène. La quinagolide est un inhibiteur de la prolactine approprié qui s'administre quotidiennement sans inconvénient par voie orale. Le stéroïde sexuel ou l'androgène peuvent être une testostérone ou un ester de la testostérone, pouvant être administré oralement ou par injection ou encore se présenter sous l'aspect d'un implant sous-cutané. L'invention concerne également une technique visant à déclencher un azoospermie chez des mâles en bonne santé.
PCT/GB1999/001948 1998-06-20 1999-06-21 Contraceptif masculin renfermant un inhibiteur de la prolactine et un steroide sexuel Ceased WO1999066935A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU43825/99A AU4382599A (en) 1998-06-20 1999-06-21 Male contraceptive comprising a prolactin inhibitor and a sex steroid

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9813278.0 1998-06-20
GBGB9813278.0A GB9813278D0 (en) 1998-06-20 1998-06-20 Male contraceptive

Publications (1)

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WO1999066935A1 true WO1999066935A1 (fr) 1999-12-29

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004082570A3 (fr) * 2003-03-17 2005-01-27 Bayer Healthcare Ag Diagnostics et traitements contre des maladies associees au recepteur d2 de la dopamine (drd2)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4210644A (en) * 1978-02-23 1980-07-01 The Johns Hopkins University Male contraception
US4381298A (en) * 1981-10-13 1983-04-26 Coulson Patricia B Oral male contraceptive composition
WO1991000095A1 (fr) * 1989-06-27 1991-01-10 Michael Cohen Preparations utiles comme contraceptifs chez l'homme
WO1998031368A1 (fr) * 1997-01-17 1998-07-23 R.P. Scherer Limited Formes et procedes pharmaceutiques destines a ameliorer les dyserections chez l'homme

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4210644A (en) * 1978-02-23 1980-07-01 The Johns Hopkins University Male contraception
US4381298A (en) * 1981-10-13 1983-04-26 Coulson Patricia B Oral male contraceptive composition
WO1991000095A1 (fr) * 1989-06-27 1991-01-10 Michael Cohen Preparations utiles comme contraceptifs chez l'homme
WO1998031368A1 (fr) * 1997-01-17 1998-07-23 R.P. Scherer Limited Formes et procedes pharmaceutiques destines a ameliorer les dyserections chez l'homme

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PIERINI A A ET AL: "EFFECTS OF BROMOCRIPTINE ON PROLACTIN AND TESTOSTERONE LEVELS IN MALE IMPOTENCE", INT J FERTIL, vol. 24, no. 3, 1979, USA, pages 214 - 216, XP000852935 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004082570A3 (fr) * 2003-03-17 2005-01-27 Bayer Healthcare Ag Diagnostics et traitements contre des maladies associees au recepteur d2 de la dopamine (drd2)

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GB9813278D0 (en) 1998-08-19

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WO1999066935A1 (fr) Contraceptif masculin renfermant un inhibiteur de la prolactine et un steroide sexuel

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