Postgraduate Medical Journal (April 1975) 51, 200-208.

Hormonal mechanisms in the onset of puberty

RONALD S. SWERDLOFF* WILLIAM D. ODELLM.D. M.D., Ph.D.

Division of Endocrinology, Harbor General Hospital Campus, U.C.L.A. School of Medicine, U.S.A.

SummarySexual maturation is associated with increasing levelsof sex steroids. These steroidal events are the result ofcomplex changes that occur at several functional levelsincluding the hypothalamus, pituitary, gonad andadrenal gland. These changes, as outlined in Table 3,are often interrelated.

While considerable progress has been made in ourunderstanding of the hormonal events associated withsexual maturation, many important questions remainunanswered. Further intensive investigation will berequired before we have a lucid understanding of thephysiological basis of the sequence of hormonal eventswhich occur during the pubertal process.

Sexual maturationThe transformation of a sexually immature child

into an adult capable of normal reproductive com-petence is the result of a complex series of hormonalevents. The sequence of development of the manyphysical changes associated with puberty have been

Height spurt I U9 5 - 14 5

Menarche U10-16 5

Breast 2Q 3& #4 58-13 13-18

Pubic hair 211111111311111114 11111111111115

e 9 10 11 12 13 14 15 16 17

Age (years)FIG. 1. Sequence of development of physical changesassociated with puberty in girls. The numbers 2-5 referto the Tanner stages of pubic hair and breast develop-ment (with permission from Marshall and Tanner, 1970).

* Recipient of USPHS Career Development Award #5K04 HD 70436-02.

I I I I >Apexstrength spurt

Height spurt II10-5 - 16 13 5 - 17 5

Penis10 5-14-5 12'-5-16-5

Testis9 5 - 13 5 13-5- 17

Gonadal rating 2'3 M4 5

Pubic hair 21llI1IIIIlII3IIIIIII4lIlIIIIlII5llIlIIiIiIii

8 9 10 11 12 13 14 15 16 17

Age (years)

FIG. 2. Sequence of development of physical changesassociated with puberty in boys. The numbers 2-5 referto the Tanner stages of pubic hair and genital develop-ment (with permission from Marshall and Tanner, 1970).

carefully documented by Marshall and Tanner (1969,1970). The physical changes which occur over a timespan of several years have been subdivided intoseveral stages for simpler discussion of chronology,relationship to hormonal changes and diagnosis ofabnormal maturational development. The widelyused classification system of Marshall and Tanner(1969, 1970) actually represents two classificationsbased on separate but interrelated events, e.g. pubichair and genital development in the male. Figures 1and 2 represent the chronology of these stages inboys and girls during the past two decades in England.Efforts have been made by several groups to developa composite staging system to allow for easiercorrelation with hormonal events (e.g. Winter andFaiman, 1972a). Similar classification systems usedin our clinics are presented in Table 1 and 2. Theages of children in whom these pubertal stages areobserved differ depending on the geographical andnutritional environment of the children. The latterfactor has been proposed as the explanation for thetrend toward the earlier development of menarche(Tanner, 1962; Frisch, 1972) observed over the pastcentury.

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Hormonal mechanisms in the onset ofpuberty

TABLE 1. Composite stages of sexual development inmales

Stage Description

P-1 Preadolescent; largest testes diameter < 2-4cm; no pubic hair or penile enlargement

P-2 Sparse pubic hair, mainly at base of penis;testis diameter 2-43-2 cm; scrotal skinreddened; little penile enlargement

P-3 Pubic hair darker, coarser, but limited in dis-tribution; early penis enlargement; sparseaxillary hair; testes diameter 3-3-40 cm;scrotal skin darker

P-4 Adult pubic hair; moderate axillary hair;testis diameter 4 14-5 cm

P-5 Adult secondary characteristics; testis dia-meter greater than 4-5 cm

Adapted from Marshall and Tanner (1970) and Winterand Faiman (1972a).

TABLE 2. Composite stages of sexual development infemales

Stage Description

P-1 PreadolescentP-2 Breast budding; early labial hair growthP-3 Increased breast size with palpable glandular

tissue; no separating of breast contours;moderately dark coarser labial hair overmons pubis

P-4 Further enlargement of breasts with projec-tion of areola above breast plane; lateralspread of pubic hair

P-5 Adult breast size and pubic hair distribution

Adapted from Marshall and Tanner (1969).

Hormonal events in pubertyWith the exception of gonadal size, most of the

visible changes associated with puberty in both sexesare due to increased production of steroid hormones.These hormones are secreted directly by the gonadsand adrenals or are converted from precursor steroidssecreted by the adrenals. In the male, pubic, axillaryand facial hair, phallic enlargement, change inmuscle mass and epiphyseal closure all result fromincreasing concentrations of androgens. Theseandrogens are predominantly produced by thetestes, but a small contribution is due to the directsecretion of weak androgens and androgen pre-cursors from the adrenal glands. In the female,breast development, female fat distribution, vaginaland uterine development, linear growth velocity andskeletal maturation are the result of increasingoestrogen secretion by the ovary. The mechanism bywhich increased production of adrenal androgens(adrenarche) occurs at puberty is incompletelyunderstood. The gonads are under the control of thepituitary gonadotrophic hormones (LH, ESH and

possibly prolactin). Secretion of LH and FSHdepends on the stimulatory effects of the hypo-thalamic releasing hormone, GnRH (Schally, Kastinand Arimura, 1971). GnRH secretion is regulated byhypothalamic monoamines such as norepinephrine,dopamine and serotonin (Kamberi, Mical andPorter, 1971). Higher CNS structures undoubtedlyinfluence the production of the latter substances.Both hypothalamic and pituitary function are

influenced by the gonads. In the male, testosterone,dihydrotestosterone, oestradiol and perhaps othergonadal substances act via negative feedback toinhibit the secretion ofLH and FSH (Swerdloff et al.,1973; Walsh, Swerdloff and Odell, 1973a, b). It islikely that this negative feedback occurs both at thehypothalamic level (inhibiting the secretion ofGnRH) (Smith and Davidson, 1967) and at thepituitary level (Wollessen et al., 1974; Vera, Swerd-loff and Odell, 1974) inhibiting the effects of GnRHon LH and FSH secretion. Thus, in a normal adultmale, castration results in increased secretion of LHand FSH owing to the absence of the inhibitoryeffects of gonadal steroids. Treatment of such aperson with androgens and/or oestrogens results in areturn of these gonadotrophins towards normal. Thefeedback system for the male is depicted in Fig. 3.

Extrohypothalamic EnvironmentCNS

+ Cyclic | Tonicarea area

+ Catecholomines

GNRH - Metaboliceffects

PituitaryFSH LH

Testis

sExtrogonodal . T+DHT;E2+ X Degrsdativesources ~~~~~~systemsFIG. 3. Hypothalamic-pituitary-gonadal feedback systemof the male. The extragonadal sources of androgen re-ferred to include androgens and androgen precursorsproduced by the adrenal glands. The testis directlysecretes testosterone, dehydrotestosterone and oestradiol.Other substances have been postulated to be secreted bythe testes which are believed to have an influence on FSHsecretion. Such a substance referred to as )X' in thediagram has been given various names including'inhibin'.

In the female (as in the male), a tonic negativefeedback system exists and ovarian steroids (oestro-gen and progesterone) inhibit LH and FSH secretion

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R. S. Swerdloff and W. D. Odell

(Odell and Swerdloff, 1968; Swerdloff and Odell,1969). This inhibitory influence probably occurs atboth hypothalamic and pituitary levels. In addition,the female has a positive feedback system (Fig. 4)by which oestrogens stimulate LH secretion (Swerd-loff and Odell, 1969; Yenn, 1971). Progestogens maysynergize with oestrogens in this stimulatory actionon LH secretion and they may be necessary forstimulation at midcycle (Odell and Swerdloff, 1968;Swerdloff, Jacobs and Odell, 1972a). This stimulatoryaction ofgonadal steroids results in the pre-ovulatorysurge of LH and FSH observed at midcycle.

Folliculor LuteolphI e p e

- Iphase phase

E

E

Degradative, systems- Metaboliceffects

E

E

FIG. 4. Hypothalamic-pituitary-gonadal feedback systemof the female.

Figure 5 depicts the cyclic changes of serum LH,FSH, oestradiol and progesterone during a normalmenstrual cycle (Abraham et al., 1971). The follow-ing sequence of events occurs. FSH rises early in thecycle and stimulates growth of the ovarian follicle.The growing follicle secretes increasing amounts ofoestradiol (and 17-a-hydroxy-progesterone). Whenthe oestradiol concentration reaches a critical level,it triggers release of large quantities ofLH and FSH.Ovulation then occurs and a corpus luteum develops.Progesterone concentrations, which begin to rise justbefore the midcycle LH peak, are markedly increasedduring the luteal phase. The elevated concentrationsof oestradiol and progesterone act via the negativefeedback system to inhibit secretion ofLH and FSH.Finally, as the function of the corpus luteumdiminishes, serum oestradiol and progesterone levelsfall and menstruation occurs. This decrease ingonadal steroids is then followed by a rise in serumFSH, thereby initiating another cycle. For completesexual maturation to occur, this entire system mustbe functional. The remainder of this paper will dealwith the hormonal events that lead to sexualmaturation.

E

F1

300 -

200

100-E2

60

40r

15 - LH j1

10 ,

514 10 14 20 28

Davs

FIG. 5. Daily serum LH, FSH, oestradiol-17B and pro-gesterone concentrations in a normal menstrual cycle(with permission from Abraham et al., 1971).

GonadotrophinsUntil recently, most physicians believed that the

prepubertal child was not able to secrete gonado-trophins. It was believed that puberty was initiatedby the onset of LH and FSH secretion. This thesiswas proved to be incorrect by the demonstration,using radioimmunassays, that LH was present in theserum ofall children (Odell, Ross and Rayford, 1967).The above finding was confirmed by the same groupof investigators using the mouse uterine weightbioassay. They showed that biologically activegonadotrophins were present in the urine of pre-pubertal children (Rifkind, Kulin and Ross, 1967).

202

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Hormonal mechanisms in the onset ofpuberty 203

7oo-: f Tetosfterone500-,-.400 4ii00lr--''-

tao

4 -

6

_2446 8 -10 12. K -14 18 20 22

Age {(years)

FIo. 6. Cross sectional data demonstrating the changesin testis size and serum LH, FSH, and testosterone duringsexual maturation in boys (with permission, adaptedfrom Winter and Faiman, 1972a; Faiman and Winter,1971).

Since that time, the pattern of serum LH and FSHduring sexual maturation has been published bymany laboratories.Serum FSH is now known to be present in high

concentrations in the serum of the fetus, the concen-trations actually decreasing as term is reached(Grumbach and Kaplan, 1973). Serum LH and FSHhave been detected at birth. In one study, FSH con-centrations in girls were elevated in the first 2 yearsof life, reached a nadir at about age 6-8 and thenincreased again during puberty (Faiman andWinter, 1971). Figures 6 and 7 show representativedata for serum LH and FSH during sexual matura-tion in both sexes (Winter and Faiman, 1972a;Faiman and Winter, 1971; Jenner et al., 1972). Serumgonadotrophins rise during maturation, serum FSHlevels increasing to a greater degree than LH in theearly stages of puberty (Faiman and Winter, 1971;Jenner et al., 1972; Penny et al., 1970). In the female,serum gonadotrophin levels eventually begin todemonstrate the cyclic pattern of the adult, but thisis preceded by a change from the pattern of constantsecretion of the prepubertal child to the pulsatile orepisodic secretion of gonadotrophins of the adult(Rubin et al., 1972; Boyar et al., 1973). The pulsatilepattern is heralded at about stage III of puberty by a

60.

g- 40

U0

3

..S '.,.*', I.'.Ng:

''

.. ...

iA. ; ;0 ;..:::S:. .... .,

: ;- : ct; ;j.. ... ..

.......:::. ...i. : ' .

" 8i. -ii5f4 13;

FIG. 7. Cross sectional data demonstrating the changesin serum LH, FSH and oestradiol during sexual matura-tion in girls (with permission, adapted from Jenner et al.,1972).

striking sleep-associated release of gonadotrophinsthat has not been found in either the prepubertal childor in the adult (Boyar et al., 1972).What causes the increase in blood LH and FSH

observed in children? Several possibilities exist. (1)A maturation process occurs in the hypothalamuswhich results in an increasing capacity to secreteGnRH and/or decreasing sensitivity to the inhibitoryinfluences of gonadal steroids on GnRH secretion;(2) the pituitary becomes more responsive to theeffects of GnRH and secretes increasing amounts ofgonadotrophins; (3) areas of the central nervoussystem outside the hypothalamus mature and modifyhypothalamic function resulting in the changes listedin (1) above. It is noteworthy that in female rats andcattle sexual maturation can occur without detectableincreases of LH concentrations (Odell, Hescox andKiddy, 1970; Swerdloff, Jacobs and Odell, 1972b)and that in the rat of both sexes, serum FSH actuallyfalls during sexual maturation (Swerdloff et al.,1971; 1972b).

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204 R. S. Swerdloff and W. D. Odell

600

500- <

400 .

1dao-a 300- //

200 /

100- g- -' <.--

OCPre. Post. Pre. Post.

10 days old 75 doays old

FIG. 8. Effect of castration on serum LH and FSH con-centrations in the immature (10 days old) and mature(75 days old) male and female rat.

Experiments in animals have demonstrated thatthe prepubertal gonad has a restraining influence onthe secretion of gonadotrophins, i.e. castration ofthe immature rat results in a prompt rise in serumLH and FSH (Swerdloff et al., 1971) (Fig. 8). In theprepubertal human, the gonad also functions as apart of a dynamic feedback system: thus serum LHand FSH levels are elevated in the serum of agonadalchildren before the time when puberty would norm-ally have occurred (Winter and Faiman, 1972b).For reasons which are not understood, serum LHand, to a lesser degree, FSH levels in agonadalchildren do not reach the levels found in castratedadults until the individual attains the chronologicalage usually associated with normal pubertal develop-ment. That is, although serum gonadotrophins in theagonadal child are usually higher than in childrenof the same chronological age they increase furtherat about the age of 12 years. This change may be dueto inherent hypothalamic maturation or due tochanging pituitary sensitivity to secreted GnRH (seebelow). Having demonstrated that the gonads exertan inhibitory influence on the hypothalamic-pituitary axis before puberty, the question arises asto why the normal immature child with low circulat-ing gonadal steroids does not have higher serumgonadotrophins. Data have been presented in experi-mental animals* (Byrnes and Meyer, 1951; Ramirezand McCann, 1963) and to a limited extent inhumans (Kelch, Kaplan and Grumbach, 1973) whichindicates that the immature hypothalamus is more

* Most investigators believe that the immature rat is moresensitive than the mature rat to feedback suppression ofgonadotrophins by gonadal steroids. In our laboratory wehave consistently observed this phenomenon for FSH. In ourstudies the effects on sexual maturation of changing feedbacksensitivity of LH in the rat remain less certain.

sensitive than the adult hypothalamus to the in-hibitory effects of gonadal steroids. Thus, a givencirculatory level of gonadal steroid appears to havegreater inhibitory influence on gonadotrophin secre-tion in the child than in the adult. One theory ofsexual maturation is that the initiating event inpubertal development is an increase in the hypo-thalamic threshold for negative feedback: withincreasing age, the 'gonadostat' becomes pro-gressively less sensitive to the suppressive effects ofsex steroids, resulting in increasing secretion of LHand FSH**. It must be emphasized that while at thepresent time this effect on the secretion of LH andFSH is presumed to occur at the hypothalamic level,this has not been directly assessed, as adequatetechniques for measurement of serum GnRH duringsexual maturation are not yet available.The role of the pituitary gland in the maturation

process has been investigated in humans and inexperimental animals. In studies of humans, syn-thetic GnRH has been administered in differentdoses to prepubertal, pubertal and adult subjects.Roth, Grumbach and Kaplan (1973) demonstratedan increasing release of LH after GnRH administra-tion with progressing sexual maturation in boys(Fig. 9). These data indicate that increasing GnRHlevels and increasing pituitary response to GnRH

I Mean + s.e. 6(o

() Pvalue 0)

_J

c

4 EC

I-J

C00

,r EE

(<0o001) (0-02)

Prepubertal Pubertal AdultFIG. 9. Comparison of mean maximal increase in serumLH in prepubertal, pubertal and adult males followingLRH administration (with permission from Roth et al.,1973).

** It is of note that there is a species difference in thisregard, in that the pattern of gonadotrophins in the rat andcow differs from that in humans. In the male rat LH risesslowly throughout maturation while FSH falls (Swerdloffet al., 1971). In the female rat (Swerdloff et al., 1972b) and incattle (Odell et al., 1970) LH levels do not appear to change.

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Hormonal mechanisms in the onset ofpuberty 205

might be factors responsible for sexual maturationin boys. In contrast to the release of LH, the incre-ment in FSH response above baseline was not in-creased by age: thus, in their study and in that ofJob et al. (1972), the prepubertal boy has a higherserum FSH to LH ratio after GnRH than does theadult.Another aspect of the mechanism of onset of

puberty in the female is the maturation of the posi-tive or stimulatory feedback response to oestrogenthat is required for the pre-ovulatory LH and FSHsurge depicted in Fig. 5. Sufficient data are notavailable to establish whether the development ofpeak LH responses (as seen before ovulation) in thematuring female requires increased sensitivity of thehypothalamus to the stimulatory influence of oestro-gen or is simply the result of gonadal steroidsreaching a threshold level for positive feedback ofgonadotrophin secretion. Winter and Faiman (1973)have evaluated the sequence of hormonal changesthat occurred at about the time of menarche in asmall group of girls. They found that oestrogenconcentrations began to develop some cyclicitybefore menarche but they were not associated withan LH surge. Menarche actually occurred before thefirst ovulatory cycle and appeared to be related tofluctuating oestrogen levels. In the period followingmenarche, the amplitude of cyclic oestrogen eleva-tions increased and ultimately LH surges wereinduced and ovulation occurred.

Role of the gonad in the maturation processUntil recently, it was generally believed that the

gonad played a rather passive role in sexual matura-tion-that is, that hormone secretion by the gonadwas entirely determined by the amount of gonado-trophic hormone it was exposed to at any particulartime. Recently, evidence has been obtained thatindicates that the gonad (at least in the male) alsoundergoes maturational changes, becoming pro-gressively more sensitive to stimulation by gonado-trophin during pubertal development. Studies in ourlaboratory have demonstrated that 5 days afterhypophysectomy the testis of the immature rat doesnot respond to administered LH (Swerdloff et al.,1972b; Odell et al., 1973). This observation, whichcontrasted markedly with the effects of LH insimilarly treated adult animals, led us to suspectthat the immature gonad of intact animals might alsobe less capable of responding to the stimulatoryeffects of pituitary hormones.

In subsequent studies in intact male animals, wedemonstrated that immature rats secrete much lesstestosterone after a single dose ofLH than do adults.The response progressively increased with increasingage and finally reached adult levels (Odell et al.,1974) (Fig. 10). The mechanism underlying the

increasing response to LH is unclear but we havefound that FSH administration to the previouslydescribed hypophysectomized immature rat returnsLH-stimulated Leydig cell function towards normal(Odell et al., 1973). More recent studies havedemonstrated that treatment of immature intact ratswith FSH results in increased serum testosteronelevels (reflected by increased ventral prostate weight)and significantly augments testosterone secretion inresponse to LH. Data in man appear to support thisconcept of gonadal maturation. Diminished respon-siveness of the prepubertal testis to HCG has beendemonstrated (Saez and Bertrand, 1968; Fraser,Gafford and Horton, 1969; Winter, Taraska andFaiman, 1972; Sizoneko, Cuendet and Paunier,1973) with the magnitude of testosterone responses inboys increasing with age (Winter et al., 1972). WhileWinter et al. (1972) found the testosterone responseto HCG correlated both with basal LH and FSHlevels, Sizonenko et al. (1973) reported that theresponse to HCG correlated better with basal serumFSH concentrations.

1700 30 g/ 100 gm BW

1600

1400

12000

! 1000E

800

600- Lg0 0g/I0gmBW

400) 400

200

10 21 41 62

Age (days)

FIG. 10. Percentage increase in serum testosteroneplotted against age of intact male rat for two doses ofNIH-LH-B7. Note that for both doses, with increasingage, a greater change in serum testosterone occurred inresponse to a constant dose ofLH (with permission fromOdell et al., 1974).

The observation that in boys serum FSH levels riseearlier than LH and that both precede the steepincrease in serum testosterone suggests that an

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206 R. S. Swerdloffand W. D. Odell

TABLE 3. Hormonal events associated with sexual maturation

Hypothalamic-pituitary axis Reduing sensitivity of hypothalamus(and pituitary ?) to negative feedback |by gonadal steroids

Increasing capacity to secrete gonado-trophins (non-feedback related) Increasing levels ofserum LH and

Pubertal sleep-induced episodic release FSHof LH

Development of adult pattern of episodicrelease of gonadotrophins

Increasing pituitary response to GnRH J

Development of positive feedback re- Cyclic preovulatory gonadotro-sponse to gonadal steroids in females phin surge resulting in ovula-

tionGonads Increasing gonadal sensitivity to gona-

dotrophins (in males)Increasing gonadal steroid secretion Increasing serum levels of gonadal

associated with increasing gonadotro- steroids and adrenal androgensphin levels

Adrenal Increasing adrenal secretion of androgens J

important sequence of maturational events may beoccurring. Fewer data are available on whether theovary undergoes similar maturational changes.

AdrenarcheThe development of pubic and axillary hair in the

female is believed to result from increasing produc-tion of androgens, which are largely derived fromadrenal precursors. During puberty, plasma dehydro-epiandrosterone (DHA), dehydroepiandrosteronesulphate (DHA-S), and A4 androstenedione allincrease several-fold, while plasma testosteroneincreases more modestly (Saez et al., 1972; Frasierand Horton, 1966; Gandy and Peterson, 1968;Forest and Migeon, 1970). Since DHA and DHA-Scan be converted peripherally to androstendione(Loriaux and Noall, 1968; Drucker et al., 1972) andandrostendione can be converted peripherally totestosterone (Horton and Tait, 1966), the increasingconcentrations of these steroids provide a physio-logic basis for the occurrence ofadrenarche. Evidencefor an adrenal source of these androgen precursorsincludes the observations that the increased plasmalevels of DHA, DHA-S, and androstendione seenduring sexual maturation can be suppressed bytreatment with dexmethasone (Rosenfield, 1971).The secretion of these steroids can be stimulated inprepubertal children by the administration ofACTH(Rosenfield, Grossman and Ozoa, 1971). Thisobservation suggests that the increase in serumconcentrations of these steroids in the maturingchild could be due either to increasing secretion ofACTH or to changing adrenal responsiveness tocirculating ACTH. Increasing ACTH secretion seemsan unlikely cause of adrenarche as cortisol and aldo-sterone secretion (when corrected for body mass) do

not increase during puberty. In contrast, alteredadrenal response to ACTH is suggested by theobservation that the ratio of androstendione toDHAand DHA-S is different in normally maturing childrenfrom that in prepubertal children receiving exogenousACTH (Rosenfield et al., 1971; Rosenfield, 1971).The mechanism by which this change takes place isunknown; perhaps changing enzymatic activity inthe adrenal gland results in increased adrenalandrogen synthesis by shuttling steroid precursorsinto pathways of androgen biosynthesis.

Integration of maturational eventsMost of the observable manifestations of sexual

maturation are due to increasing blood levels of sexsteroids. The mechanisms by which the secretion ofthese hormones increase at the time of puberty arecomplex and involve maturation of the hypothala-mus, pituitary, gonad and adrenal glands. Thesechanges and their interrelationships are outlined inTable 3.

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