The Principles and Practice of Hormone Therapy in Gynaecology and Obstetrics [1 ed.] 9783110006148, 3110006146

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Joachim Ufer Hormone Therapy jn G ynaecology and

bstctrics

In an endeavour to provide the doctor with information on the advances in endocrinological research and practice, we have made available for free distribution part of this edition of "Hormone Therapy in Gynaecology and Obstetrics". In this way we hope to make a contribution to modern gynaecological hormone therapy. SCHERING AG Berlin

Th Ptin ipl " and Pra i

f

Hormone Therapy in Gynaecology and Obstetrics li y

Dr. J oachim

fer

82 Figures

\Xi' a I t: e r d G r u y t r & ' o. vo nnal s G . J. Goschcn'sch · Vcrlagshandlung J.

Gu tt cntag, Vcrlagsbuchhandlung Georg Reimer -- Karl J. Tr(ibnc r - \l l·it &

Berlin 1960

o mp.

Copyright )968 by Wa lt.er Jc Gruytcr & Co,, vo rmal s G . J. Gi:\schcn' sc hc Vcrla11shandl111111 - J. Gutmllag, Vc:rlagsb11chhandlu11g · (;w,g Reime r · Ka rl J, Trllhncr · Veit & Comp., Jlcrlln 30 - All riRhts re ervcd. - Archi,•- Nr , 181 67 1 - l'dntccl In ,cr many :iatz un..-ual Maturity V. Pregnancy. VI. Delivery and Lactation VII. Climacterium . VIII. Post-Climacterium and Old Age

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H 36

VII

Table of content s G. Therapeutic Use of Hormones . T. General Pr inciples . . a) Substitution Therapy b) Stimulation Therapy c) Suppression Therapy d) Loca l Treatment . . e) The Use of Sex Hormones in ExtraGenital Disorders . . . . . . . . lT. Biological Evaluation anJ '!\:st ing of Hormones . . . a) Oestrogens . b) Progestogens c) Androgens . d) Gonadotrophic Hormones . 11 I. Methods of Administration a) Steroid Hormones 1. Implants . . . 2. Injections . . 3. Oral Therapy 4. Local Treatment 5. Vaginal Application . 6. Rectal Application . b) Ovarian Extracts . . . . c) Gonadotrophic Hormones IV. Side Effects of Hormone Therapy and their Prevention . . . . . . . . . a) General Non-specific Side Effects b) Local Non-specific Side Effects . c) Specific Side Effects due to O estrogens . . . . . . . . . d) Oestrogens and the Formation of New G rowths. e) Progestogens . f) Androgens . . g) Gonadotrophins h) Corticoids. . . V. Concerning the Choice of Preparation. a) Sex Steroids . . . . . . . . . . b) Preparations with Gonadotrophic Actions. . . . . . . . . .

111. Clini ca l Investigation . a) Diagnostic Curettage.: h) Culdoscopy . . . . c) Exploratory Laparotom y lV. Investigations Requiring Complcx Laboratory Eq uipm ent (Hormon e Assays) . . . . . . . . a) Oestrogens in Urine . . b) Pregnanediol in Urine c) 17-Ketosteroids in Urine cl) Gonadotrophic Hormones . e) Human Chorionic Gonadotrophin in Serum or Urine . . . . f) Corticosteroids in Urine. . . . . .

38 38 39 39 39 40

40 40 40 42 42 43 44 44 44 44 45 45 45 46 46 46 46 46 46 47 47 47 48 48 49 49 49 50

H . Diagnosis of Endocrine Disorders . 51 I. Simple Measures (no laboratory facilities 51 required) . . . . . . . . . . a) History . . . . . . . . . . 51 b) General and Gynaecological 52 Examinations . . . . . . . c) Basal Body Temperature . . 53 d) Diagnostic Tests using Hormones 54 e) Examination of Cervical Mucus 55 f) Endometrial Biopsy . 55 g) Hysterosalpingography . . . . 56 h) Skull X-rays . . . . . . . . 56 II. Investigations Requiring Modcst Laboratory Equipment . . . . 56 a) Biological Pregnancy Test (Frog 56 Test) . . . . . . . . . . . . b) lmmunologi.cal Pregnancy Tests 57 c) Vaginal Cytology . . . . . . 58 d) Assessment of Hypothalamic and Anterior Pituitary Function . . 59 e) Examination of Sex Chromatin. . 60

J.

6r 6r 61

62

62 63 63 64 65

65 67

Pubertal D isturbances and their Treatment 69 I. Precocious Puberty . . . . . . . 69 II. Delayed Puberty . . . . . . . 69 a) Ovarian Agenesis or D ysgenesi s 70 b) Dwarfism . . . . . . . . . . 70 c) Pubertal Obesity . . . . . . . 71 III. Abnormalities of Menstruation in Puberty 71 a) Delayed Menarche . . . . . . . . 71 b) Abnormal Menstrual Rhythm . . . 71 c) Hypermenorrhoea, Polymenorrhoca 71 d) Pubertal Menorrhagia. 71 IV. Gigantism . . . . . . . . . . . . . 72

K. Treatment of Gynaecological D isorders in Sexually Mature Women I. D isturbances of Menstruation a) Classification b) Hormones to Control or Stimulate Bleeding c) Amenorrhoea 1. Types of Amenorrhoea 2. D iagnosis and Treatment of Amenorrhoea . 3. Special Comments. 4. Primary Amenorrhoea . 5. Secondary Amenorrhoea . 6. Conclusions about the Treatment of Amenorrhoea 7. Amenorrhoea with Uterine Hypoplasia 8. "Silent Amenorrhoea" . 9. Amenorrhoea with Polycystic Ovaries 10. Amenorrhoea in Cases of Ad renogenital Syndrome . 11. Post-partum Amenorrhoea . 12. Amenorrhoea and Galactorrhoea 13. Amenorrhoea with Dwarfism and Ovarian Failure . cl) Dysfunctional Bleeding with Persistent Cystic Follicles. e) The Anovulatory Cycle . f) Disturbances of Rhythm in the Presence of Ovulation . 1. Oligomenorrhoca . 2. Polymenorrhoea

73 73 73 74 75 75 76 77 77 78 82 82

83 83 84 85 87 87 8S 91 91

92 93

VIII g) Abnormnl l3I ecling nt Reguhtr ln tervn ls . . . . . . . . • • 1. Ov ulntory Bleedi ng . . 2. Prem nstrunl 13lced ing . 3. P stmenstru11l Bleeding 4. Hypenn norrhocn . 5. Hypomeno rrhoc:1 . . h) D ys meno rrhoea . . . . i) Premenstrual Syndrome. 11. Hypoplasia of the Genital T ract . Il I. lntersexual States . . . . . . . IV. Infertility . . . . . . . . . . a) Infertility with G enital T ract H ypoplasia . . . . . . . . . . . . . . b) Infertility due to Failure of O vulation c) lnfertilitiy due to Corpus Luteum Insufficiency . . . . . . . . . d) Infertility due to Early Abortion V. Hormones for Contraception . . . VI. Frigidity . . . . . . . . . . . VII. Disorders of Pregnancy and the Puerperium . . . . . . a) Abortion . . . . . . . b) Premature Labour . . . c) Hyperemesis Gravidarum d) Pre-eclamptic Toxaemia . e) Diabetes and Pre-eclampsia f) Ectopic Pregnancy . g) Hydatidiform Mole. . . . h) Chorion-epithelioma . . . i) Control of Uterine Contractions by Sex Hormones . . . . . . k) Control of Lactation . . . I) Post-partum Endometritis . VIII. Organic Disorders a) Fibroids . . . b) Endometriosis . c) Mastodynia . . d) Fibro-adenosis . c) Mammary Hypoplasia and Hyperplasia. . . . . . . . f) Pelvic Inflammatory Disease . . . .

L. Treatment of Climacteric Disturbances and the Sequelae of Castration . . . . . . . .

T nblc of contents

94 94 94 95 95 95 95 96 97 98

J. Disturbnn cs be fo r · th e Menopau e . 11. Di sturb11n cs after t he Mcnnpaus · . 111 . Cnstra tion . . . . . . . . . . . .

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M. Treatment of Disturban ces Ari s ing Afte r the Cllmacterium . . . , . , . . . . , 12 I. V:ig in al Changes in Elderly Women . r2 II. Pruri tus :i nd Kraurosi s Vu lvae 12 5 ] I l. Pyo mctra . . . . . , r2 5 IV. Climacteric T ri goni ti s . 125 V. Stress Incontinence . , 1 25

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II 3 11 3 114 1 15

N . Hormone Therapy for Carcinoma 12 6 I. Mammary Carcinoma , , 1 26 a) Introductory Remarks . 1 26 b) Castration . . . . 127 c) Adrenalectomy 127 cl) H ypophysectomy 127 e) Treatment with Anabolic Stero ids or Testosterone Esters . . . . 1 28 f) Treatment with Oestrogens r 28 g) Treatment with Cortisone . 128 h) Progestogen Therapy . 12 8 i) Management 129 II. Uterine Carcinoma . . . 1 29 a) Carcinoma of the Cervix . 1 29 b) Carcinoma of the Co rpus Uteri . 130 III. Carcinoma of the O vary . . 1 30

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r 16 117

0. Hormone Producing Tumours I. Tumours of the Ovary . . II. Adrenal Cortical Tumours . III. Tumours of the Anterior Pituitary

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P. Hormone Therapy with Gynaecological Operations . . . . . . . . . . . . . I. Treatment of Post-operative Shock II. Hormone Therapy before Major Operations . . . . . . . . . . . III. Operations during Pregnancy. . . IV. Oestrogen Therapy with Plastic Vaginal Surgery . . . . . . . . . . . . . .

Q. Table of the Most Frequently used Hormone Preparations . . . . . . . . . .

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1 34 1 35 1 35

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Cln::::itic:iti0n

f I lo rmoni.:~

A . Classification of Horn1ones

1

I. Intr du ti on T he co ncept· of inte rn al secretio ns was introdu ced by ClaNde /Jernard. He descri bed it as th e process w h reby certain. ce ll contro l vital processes and ph ys io log ical activity at remote sites by excreting o rgani c su bsta nces into tiss ue fluid. Ba)lliss and Starling later called these substances hor111ones. We recog ni se not o nly hormones which are produced by end ocrin e glands (and enter the circulation without passing through a duct), but also secretions from exocrine glands which do have ducts. The latter will not be considered in this book although the substances they produce resemble hormones in that they both, in relatively small amounts, can influence many physi ological processes by a catalyst-like action.

II. Steroid Hormones Steroid hormones are derived from 'S terane' and are soluble in fat. T hey are formed by the gonads, the adrenals and the placenta. Table

1.

O vary

+ + + + + -

Site of Steroid Hormone Formation

I Testes I Adrenals I + + + -

+ + + + + + + +

O estrogens Androgens Progestogens G lucocorticoids Mineralocorticoids

T hey can be divided into the following groups : oestrogens, progestogens, androgens, glucocorticoids and mineralocorticoids. It should be noted that some steroids belong to more than one group.

Example : D esoxycorticosterone is a mineralocorticoid whose acetate derivative has a significant progestational action.

In addition, some steroids diminish or cancel out the effect of steroids from another group, and this phenomenon depends on the dose relationship between competing substances. Example : A t higher dosage levels, p roges togens and androgens have an anti-oes trogenic effect. The la st decade has seen so marked an increase in the number of stero ids recognised that the fo llowing subclass ifica tion is appropriate :

Classification of Hormones

2 1. 1 ahmil!J, ormrring steroid hormones formed in the adrenals gonads and the pine nta. 2. Thrir inlrrmcdimy mclabolitc.r which arc found in th blo d, th li ver o.r in urine. 3. Strroid.r oblai11rd 0, rbemit-al reaclio11.r (e.g. csteriftcntion or attachment of a methyl gro up, an th yl gro up, or a halogen atom to o ne or more carbon atoms). Although their action and structure arc related to the parent substances in groups 1 and 2, these products do not occur naturally. Their therapeutic use is, therefore, not strictly speaking, "hormone therapy".

III. Protein Hormones Unlike steroids, these substances, which are of protein character, are soluble in water. Their synthesis and purification, made difficult by their large molecular weight have, to date, only been achieved with hormones from the posterior pituitary, with adrenocorticotrophic hormone (ACTH), and insulin.

a) Hypophyseal Hormones A probable total of 10 different hormones is found in the three parts of the hypophysis cerebri (pituitary). Hormones numbered 1, 2, 4, and 5 in Table 2 are "trophic", i.e. they control the function of other endocrine glands. By contrast, growth hormone, as well as the hormones produced by the pars intermedia and the posterior pituitary exert their action on tissues directly. The primary action Table

2.

Pituitary hormones

Anterior lobe A. Gonadotrophic hormones I. Follicle stim. hormone (FSH) 2. Luteinising hormone (LH) = interstitial cell stim. hormone (ICSH) 3. Luteotrophic hormone (LTH) = Prolactin B. Hormones affecting metabolism 4. Adrenocorti cotrophic hormone (ACTH) 5. Thyroid stim. hormone (TSH) 6. Somatot rophic hormone (STH)

I Middle lobe IPosterior lobe Mclanophore stimul. hormone (Intermidine)

Antidiuretic hormone 2. Oxytocin 3. Vasopressin 1.

of prolactin (or lu teotrop hic hormone, LTH) is on the lactating breast. It is not known whether L TH has any trophic effect on the corpus lu teu m of the non-pregnant woman . In addition to the above hormones, a number of other " trophic" substances have been described e.g. diabctogenic, anti-insu lin, erythropoietic, fat-mobilising and cxophthalmic hormones. The relevant publications, some of which deal more with hypothesis than fact , have not led to universal recognition of these substances. FSH and ICSH, both of which are important in gynaecology, derived their names from their effects on gonadal function . The restricted amounts of FSH that can be extracted from human pituitaries or menopausal urine (HMG) limits the therapeutic use of these hormones.

b) Human Chorionic Gonadotrophin. (HCG) A list of protein hormones must include HCG, which is present in the urine and serum of pregnant subjects. HCG stems from the trophoblastic cells of the placenta. This hormone was originally called Prolan and the anterior pituitary was thought to be its site of production. The hormone in pregnant mares' serum (PMS) has no chemical or biological relationships with HCG. HCG, unlike the gonadotrophic hormones of pituitary origin, can be obtained in fairly large amounts. In practice HCG, rather than anterior pituitary hormone, is used to stimulate gonadal function. Whether or not "human placental lactogen" (HPL) is a further, separate protein hormone is still under debate. It is said to have luteotrophic action.

IV. Synthetic Substances with Hormone-like Actions A certain number of synthetic substances have hormonal actions although their structure does not resemble naturally-occurring hormones. They are, in a sense, substitutes, and several oestrogens are important in this respect. Stilboestrol was the first to appear, and later substances were dienoestrol, h xocstrol, benzoestrol and allenolic acid. Paraoxypropiophenone, in spite of some contradictory evidence, is a weakly oestrogenic substance (with regard to its central and peripheral act io ns). Clomiphene, known t stimulate ovulation, also belongs to this gro up.

Classification of Hormones

3

V. Anti-hormones 'Anti-hormones' may be formed in circumstances where a protein hormone from one species is repeatedly injected into an animal from another species. The name 'antihormones' is misleading as it implies that these substances have hormonal action. In fact, 'anti-hormones' are antibodies against foreign proteins. The fact that antibodies can be raised against protein hormones forms the basis for quantitative immunological assays

(see page 57). In humans, repeated injections of PMS or animal pi tuitary extracts (over a period of at least I month) lead to 'antihormone' production, which dimini shes the therapeutic action of the substances injected. It is said that after an interval of ;-6 months without treatment, antibodies can no longer be detected. HCG extracted from human pregnancy urine, does not lead to antibody formatio n when injected into humans.

Chem istr y of [ lormonc

4

B. Chemistry of Hormones

I. teroid Hormones All stero id hormones have a cycl op ·ntanophenanthrene ( tern ne) ring.

Sterane Rings A, B and C each have 6 carbon atoms while ring D has 5. The way in which the carbon atoms are numbered can be seen by studying the illustrated structure of choleste-

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rol from which all steroid hormones are formed.

Except for oestrogens and aldosterone, all naturally occurring steroids possess meth I groups attached to carbon atoms 1 0 and 13 .

Chemistry of H o rmo nes

5

For the sake of simplicity, the chemical symbols for the methyl groups arc omi tted, but their presence is indicated by a vertica l line. Accordi ng to the number of carbon atoms they possess, we recognise C18 steroids (oestrone derivatives), C10 steroids (androstane and testane derivatives) and C21 steroids (pregnane and allopregnane derivatives).

b) Progcstogcns The naturall y ccurring luteal. hormone, progestero ne, belongs to the large group of ½i steroids which includes the adrena l hormones. This is not surprising as progesterone is no t only found in the corpus luteu m, but al so occurs as an intermed iary metabolite in the adrenal.

a) Oestrogens These are oestrone (C18) derivatives . They are characterised by an aromatic A ring, the absence of a methyl group at C10 and a hydroxyl group at ½· Of the three naturally occurring oestrogens, oestradiol is the most active. Oestrone and oestriol, which are derivatives of oestradiol and are excreted in the urine, are less active.

CH3 I

c- o

Progesterone

By a process of reduction, progesterone is converted into pregnanecliol. Although the latter is inactive, its measurement in urine is of clinical interest. HO

HO

OH Pregnanediol

HO

Oestradiol benzoate, oestradiol valerate (a depot form) and orally active ethinyl oestradiol are the substances of greatest importance in therapeutic use. OH O estradiol,3-be nzoate

0-

0 II

C-0 0 I

O-C-(CH2 )J- CH3 O es tradio l -17va lera tc

Ethinyloe s tradiol

Progesterone is sparingly soluble in oil, quickly broken down, and has no appreciable depot action. It thus does not satisfy the criteria demanded of hormones for modern clinical use. It was found that oestradiol and testosterone could be rendered markedly progestogenic by esterification or introduction of an alkyl (methyl or ethinyl) group. An analogous modification of progesterone was not possible and for this reason the search for other progestational steroids began relatively early. It first led to the production of pregneninolone, an orally effective substance which has since become obsolete because of its relatively weak action. Many other progestational substances have been discovered in recent years and can be arranged, according to their structure, in 6 major groups. I. Progesterone, retroprogesterone. II. D erivatives of the 17-cx-hydro:xyprogesterone esters.

Chemi stry o ff Iormon cci

6 III. Derivatives of the 19-norh ydrox yprogesterone ester. IV. D erivatives of testosterone. V. Derivatives of 19-nortestosterone. VJ. Derivatives of deoxo-19-nortestosterone. The progestational action and side effects of each group are different (see page 2 r ). Substances of particular value in clinical use include 17-11.-hydroxyprogesterone-caproate from group II (a depot progestogen), 17-11.ethinyl- 19- nortestosterone-acetate from group V (tablets) and 6-chlor-6-dehydro-acetoxyprogesterone from group II (tablets).

The addition of a methyl group at (arrow II) led to the synthes is of an orad; active androgen, methyl testosterone. 2.

3. By the addition of an ethinyl group at C17 and removal of the methyl group at Ci 9, the powerful progestational substance ethin ylnortestosterone was obtained (arrow III). Ill

l

+-I +- II

19

16

2

Testosterone 4

6

17a Ethinyl-19nor-testosterone-· acetate

17a-HydroxyProgesteronecaproate

0

yHa

c-o

In the ovaries, adrenals and placenta, /::J,. 4androstene-3, 17-dione, a substance closely related to testosterone is found. This substance is one of the 17-ketosteroids which are characterised by the conversion of the hydroxyl radical at Ci 7 into a ketone group.

--0-