Minireview: Adrenal-gonadal interactions at puberty

PergaII~on Prean

Life Sciences Vol . 14, pp . 1623-1633 Printed in II .S .A .

MINIBSVIHW :

ADR~er ...arerener. INTSRACTIONS AT PiTBHRTTY Judith A. Ranaley

IInivereity of Nebraska Medical Center 42nd sad Devey Avenue Omaha, Nebraska, 68105

(Received in final fozm 4 March 1974)

Msturbaaces in adrenal function can produce changes in fertility.

The

relationship between adrnnocortical eecrntion and the fuactioas of the reproductive system vas the subject of a great deal of research effort is the 1950'e (see reviavs 1-3) but interest then abated until recently .

Beginning in about

1969, papers bagaa to appear on the subject of the effects of chsagee in adrenal secretion or the administration of adrenal steroids upon various procasses in reproduction including puberty (4-5), ovulation in the adult cycle (6-7),

the using and incidence of mating behavior

(6,8), conception and im-

plantation, foetal vantage (9-10) and lactation (11) . I will confine my diecuselon on adrenal-gonadal iateractionn to the effectn of adrenal status on puberty.

The reason for selecting the process of puberty

as a focus for this review is that sexual maturation consists of a series of easily measurable events . 1.

There avents are indicated diagramatically in Figure

Basically, the events leading up to the first ovulation are similar to those

in any estrous cycle but they are easier to recognize.

The first external sign

of iapeadiag ovulation at puberty ie the breakdown of the skin covering the vaginal orifice, as event called vaginal opening. In the rat the vagina rewire opened throughout thn remainder of the animal's life .

Bsrely is there more than one or two days between vaginal open-

ing sad ovulation (12) .

Ovulation in the rat takes place during the midpoint

of the dark portion of the 24 hour photoperiod.

If a rat is examined the morn-

ing after ovulation it is possible to see hemorrhagic follicles in the ovaries and a dilated loop of the oviduct on each aide, called a dilated ampulla. 1623

If

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Adrenal and Puberty

Vol . 14, No . 9

i~llss~d ~tsns rritlal ~~rl~~ 111~t~1 ~q~ll~ a~ Isr LN nlsau Is~~rrigk I~Hirl~s ~ql~d ~~sd~0 sts4~tt~~

1l00

Etrante at vubertv.

l000

l~00 0~00 tist~ ~1 ~~~

1l00

Pig. 1 Dark bare rnpreaent dark portions of 24-hour

photoperiods in which lighting schedule le maintained at 14 hours light :l0 hours dark . the oviducts are removed and squashed under a coveralip on a microscope elide, ova,

still surrounded by a cloud of follicular cells, can be easily seen . Vaginal opening, ovulation and the number of tubal ova can be used se

measures of the pubertal process .

Thane events can then be related to changes

in adrenal encrntion or to the administration of agents that either mimic adrenocortical activation or alter endogenous adrenal activity .

Por these

reasons, puberty represents a convenient model system in which to study adrenalgonadal interactions . In this review I trill eimimarize the main lines of experimentation over the past four years that have led to the concept of the adrenal cortez as a "timer" in the ovulatioy cycle, especiallq during puberty.

The theme that will emerge

ie that the timing of adrenal output of steroids can enhance or deprnas fertile ty depending upon whether the peak output of corticoids (including sea ateroida) coincides trith the critical period of the estrous cycle .

The term critical

period (13) refera to that interval oa the day of proeatroue during which ovuLstion csa be blocked by the administration of agents that interfere with hypo-

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thalamic activation of the pituitary. Once this period is passed, ovulation ca~ot again be iaducad until the following day.

It is during this critical

period that adr~al-gonadal iateractioas seem to be most important in regulating the timing of the events of puberty and of the adult ovulatioy cycle . The lines of evidence that suggest the adrenal can iaflueace the timing of puberty are simmarised in Table 1 .

Removal of the adrenal glands

(both

cortez and medulla) results in a delay is the onset of vaginal opening and ovulation (14,5) .

This delay ie oa the order of a few days and occurs despite

maintenance of the rata with 0.9 saline .

Goreki and Lawton (15) have found

TABLE 1 E~erimental Approaches on the Study of Adraaal Gonadal Interactions 1.

Definition of rhythms of adrenal activity a. Corticosteronn b . Progesterone

2.

Effects of adreaalectomy a. Normal puberty b . Puberty after ezogeaous gonadotrophln

3.

Correlation between onset of puberty and changes in adrenal rhythms.

4.

Effects of adrenal steroids in facilitating ovulation or is praventiag ovulation.

5.

Correlation between changes is fertility and changes in the adrenal rhythm .

that the effect of adrenalnct~y is demonstrable most dramatically in the period between weaning (up to 21 days of age) and 26 dayn of age.

Adrenalectomy after

26 days of age has more si~bile .effncts on puberty, resulting in a different pattern of ovulation or a change is ovarian weights but not a disruption in the time of vaginal opening.

Adranalectomy also alters the response of prepubertal

rate to eaogenoue gonadotrophina (4,16) .

Iiandl (16) first reported that adr®a].-

ectamy prior to the administration of pregnant mare's serum gonadotrophin (PMS) reduced the ovarian response in both prapubertal and adult rata . istration of cortisone restored the response to PlfS .

Daily admin-

Later, Ramaley (4) found

that small doses of PMS given to weaaliag rats would induce ovulation only if

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the adrenals were intact while is 27 day old ausmals adrenalectomy reduced the ovari.aa and uterine weight responses to PMS but did not block ovulation.Adrsaalectosy removes both adranocortical steroids and catecholaminns .

Goreki sad

Iawton (5) reported that adrenal deaedullatioa did not alter the process of puberty, suggesting that a daficieacy of hormones from the adrenal torte: was responsible for the effects of adrenalectamy. The adrenal torte: ie capable of secreting several steroids, any of which could repraenat the signal that integrates adrenal and gonadal function .

The

two main hormones that have been studied are progesterone sad corticostarone . Both of these etaroide are secreted in a cyclic manner . a daily rhythm is plasma (17-19) .

Corticosterone ezhibLts

In adults, the mazsmum conceatratioa of

corticosterone ie fovad just prior to or during the dark phase of the 24 hour photoperiod while sdaim~ levels occur during the early part of the light phase . When daily rhythms of corticoeterone are related to the estrous cycle,

there

appears to be a greater peak on the afternoon of proestrus, the day during whLch the ovulatory stage of gonadotrophia occurs .

In immature rate, a corticostesme

rhythm ie first apparent before weaning age (20) .

The nature of the rhythm

chaagae during the first few days, reaching the adult pattern by about day 26 (21) .

If the daily pattern of corticosterona is followed as rata approach

puberty, it can be seen that the amplitude increases gradually until the day of vaginal opening .

On thin day the levels of corticosterona are markedly elevated

during the daylight, at a time when they era normally minimal.

This elevation

coincides with the first proestrous period . Progesterone also ezhibite a rhythm is the blood of adult females (44) . In 1961, Taylor (23), using a histochemical technique, obtained evidence euggesttng that the immature rat ovary might be secreting progesterone as early ae 2 or 4 weeks of ag~. (24) .

Other indirect functional evidence woes also obtained by Alden

Until the recent development of a eeasitive radioimm~moassay for pro-

gesterone, it was difficult to measure the small amounts (0 .5-10 ng/ml) in the blood of prepubartal rate .

Raaalny and Hartoaik (25) recently succeeded in

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deaonetrating a daily rhythm of progesterone in the blood of 28-29 day old and 33-34 day old rats .

as

in the case of the corticosterone rhythm, the peak of

concentration of progesterone vas found at the beginning of the dark phase of photoperiod .

Induction of precocious puberty by means of PMS caused a marked

increase in the blood levels of progesterone during the period of gonadotrophia secretion is the PMS-induced puberty cycle.

We am now studying the relative

contributions of the adrenals and the ovaries is this rhythm . It can ba concluded that there is a daily rhythm of both cortlcoatnrona and progesterone, and that changes in the concentrations of these hormones omur in aasociatioa with vaginal opening and the first ovulation at puberty, whether puberty occurs normally (21) or ie induced early by means of exogenous gonadotrophin (25,26) .

An ezperiamtal model system using the prepubertal rat has

been developed to test the ability of various agents to facilitate or inhibit ovulation.

This eystm is based on the earlier observation of McCoroack and

Meyer (27) that low doses of PMS gives to weenliag rats will induce ovulation only in a small percentage of the aninaL while a "priming dose" of progesterone given an the day of proestrous (at 9 a.m . tw days after PMS) will significantly increase the number of animals that ovulate.

IIsing this syates, Ying sad Meyer

(28-30) have tented the ability of a variety of agents to facilitate the ovulatort' raaponsa to PMB .

among the cos~pounds that are effective are progesterone

sad corticoaterone, .both adreaocortical prodncta . adrenal corticoids can also bloct ovulation.

If animals are stressed

(31-33) or given injections of either adranocorticotrophic horswne (AC1H) 34) or synthetic corticoids

(31,

(34,35) on a continuous basis, puberty is delayed

and the reaponaa to PM8 blunted or eliminated (34) . The effect of ACTH requires the presence of the adrenals in rate (34) but not in mica (36) .

as we shall

see later, the different effects of adraaocortical activity can ba traced to timing of the horaona output in relationship to the events of the ovulatioy cycle. The interaction of the adrenals sad the gonads in the regulation of

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Adrenal and Puberty

fertility takes place on several levels .

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Hagiao has i~eetigated the Bite of

action of ACTH-induced adrenal secretion is blocking precocious puberty (37) . In a rat is which ovulation has been blocked by means of pentobarbital administration prior to the critical period of gonadotrophia release, electrical stimulation of the ventromedial-arcuate area or the preoptic area of the hypothalamus will override the drug block and ovulation will occur (43) . In .contraet (37), electrical stimulation of the hypothalamus will not override the effects of ACTH stimulation or synthetic corticoids .

The failure of ovulation in ACTH-

treated rata is not due to a change in the respoaeiveness of the ovaries to gonadotrophin .

Thin was ruled out by showing that direct stimulation of the

ovaries with 10 III of h~an chorionic goaadotrophin (HCG) would cause ovulation in PM3-primed rate whether or not ACTH tae also given (34) .

It has not yet

been possible to duplicate the inhibitory affect of ACTH using systemically administered corticosterone (34) .

However, a longer acting synthetic corticoid,

de~~thaeone, was effective in inhibiting ovulation given on a daily dosage schedule of 10 to 20 UB Per day intramuscularly at 9 :30 a.m . and 4 p.m . intrahypothalamic injections of deaamethaeone (4 u8 ~ 1

ul

9ma11

of diluent) placed

in the preoptic area were as effective as syate,nic injections is blocking ovulation in PM8-treated rate (34) .

Ovulation was not blocked by the same dosage of

desamathasone in the vantromedial-arcuate or mamillary areas of the hypothalamuQ Smith, et al .

(38) implanted crystalline cortisol acetate is the medial basal

hypothalamus and ware able to block gonadal maturation is r ate.

It enema lilely

on the basis of thane studies that adrenal steroids interfere with ovulation at the level of the brain. It ie poeaible to correlate shifts in adrenal rhythms with changes in fertility although this dose not, of course, prove that the two era related. One approach ie to apply a stimulus that altars the adrenal rhythm of cortico eterone and then monitor fertility .

This approach has been used by Johnson and

Levine (39) who observed that water restriction can induce a phase shift is the plasma corticostarone rhythm, abolishing the normal afternoon peak .

This puss

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shift was found to be associated with chaagne in the estrous cycles of adult rate (40) .

Estrous cycles ware prolonged and the onset of sexual behavior

occurred earlier on the day of proeetroue than normal . Aaothar approach to the study of adrenal effects on ovulation is to develop a stimulus that will alter fertility and then determine whether the adrenal rhythm has also shifted . studies .

We have applied this method in two different

Ia the first series of e:parimeats, mice were eapoead to a daily

stress conaietiag of two short daily periods of heat e~osure, immobilization or ether stress for a period of seven days .

The animals ~anre either prepubertal

(41), undergoing puberty during the stress period, adult cycling females or old (persistent estrous) adults (42) .

At the end of a v~aek of stress the fmalea

were placed with fertile males sad the incidence and timing of conception, and litter size were recorded in the adults .

In the prepubertal rate, vaginal

opening and the daily vaginal cell smear were recorded and the animals were teen placed with melee and conception and litter size anted. It became apparent that straea introduced before puberty delayed puberty and reduced fertility once puberty wsa achieved while stress after puberty caused an increase in litter size in the cycling females and induced ovulation and mating is the old, pereistent estrous adults .

Meociated with these dramatically different responses

to etrnss were different patterns of corticoeterone (10) .

In the old, non-

cycling females, a daily rhythm of serum corticoeterone was absent before the strase interval and appeared afterwards in association with a return of fertility . In the cycling adults, the rhythm inverted, bringing naaimal lavele of corticosterone in coincidence with the period of gonadotrophin secretion on the day of proeetroue .

This condition simulates the effacte of as injection of cortico-

eterone during the critical period (28-30) .

In the immature rata the rhythm

was depressed or eliminated, causing a critical drop in eextmi corticoeterone concentration during the proeetroue periods . Changea in the peripheral progesterone rhythm also correlate with fertility. If PMS ie igjected early in the light phase of the photoperiod the time of

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Adrenal and Puberty

1630

vaginal opening and ovulation ie earlier thaw if PM3 ie givm at the begi~ing of the dark period (25) .

Associated with this difference in the timing of

pubertal events, there ie a difference in thn being of steroid secretion . Peripheral progesterone and corticosterone are elevated sooner in the animals is~jected in the morning (see Figure 2 for an assample of this correlation) .

u,

a~

io " s_

~ u

uo

~ p

~ W d1~gY~

~m

~m

Fig. 2 Correlation between Progesterone and Corticostarone Rhythms on the Day of Ovulation in PMS-treated rata . P1î8 givm at 9 a.m . tw days earlier. Corticostarone is uniajected controls is shown for comparison . At this point we can aummariae the evidence that the adrenal corta: can influence ovulation.

First, hormones from the adrenal cortez cea facilitate

ovulation. This effect is more readily seen in rate before 26 days of age at a time when gonadal maturity is not complete (43) .

In these animals, an elevation

in peripheral progesterone and corticoeterona seems essential for inducing ovulation is response to PMS .

After this period, goaadal maturation is nearer

completion and the "priming" of the system with adrenal-derived asst steroids may be Teen necessary.

In the adult, fertility is not abolished in well-

maintained adrenalectomiaed rats but the timing of the ovulatioy cycle appears to ba slightly disrupted,

leading to prolonged estrous cycles

(11) .

The Le]ativa

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Adrenal and Puberty

iaaturity of the prepubartal rat model permits analysis of an interaction Which probably still occurs in the adult but which is less critical for fartßity . It sees likely that either progesterone or corticostaroaa could nerve as the phase signal from the adrenal torts:.

Although both the adrenal and the

gonads can produce progestuona, azparinants is the adult suggest that the early rise is progesterone on the day of ovulation probably tames from tba adrenal torte: rather thaw from the ovuias while the rise later is the day of proestrous represents primarily an ovarian contribution (44) .

A question that

has not been resolved as yet is what controls the adrenal response on the day of ovulation.

It weld ba particularly satisfying to assume that changes is

gaaadotrophia secretion affect both the adrenals and the gonads in a coordinated nanaar .

IInfortuaataly, aridaace regarding the effects of goaadotrophias on the

adrenal torts: has so far only bees obtained in unusual cases such as in rate with hueditary chromosomal defects (45) or in gonadotrophin-responsive adrenal tumors (46) .

At presaat there appears to be evidence that the daily pattern of

proguterone secretion by the adrenal torte: nay be regulated by a combined action of ACTH and prolactin (47) .

In certain birds which am seasonal brnedsrs,

the gonadal cycle has been related to the interactions of corticosterona and prolactia (48) sad a similar cycle of hormonal interactions could conceivably regulate the gonadal cycle of the rat.

Rising esz steroid production by the

maturing ovary may be responsible for changes in ACTH and prolactin eecretioa at puberty (49) . The mainteaaaca of continuously high corticoid eacretioa or brass concentrations of corticoid (by local infusion or implaatatioa) can block ovulation. In contrast to thin, changes is the daily rhythm that bring the peak corticoid secretion is synchrony ~rith the daily critical period appear to facilitate ovulation.

The effects of adrenal activation on fertility ss~ to depend upon

Whether an adraaal rhythm is maintalaed and upon the phaserelationshipe between the adrenal rhythm and the critical period for gonadotrophia secretion.

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REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 . 14 . 15 . 16 . 17 . 18 . 19 . 20, 21 . 22 . 23 . 24 . 25 . 26 . 27 . 28 . 29 . 30 . 31 . 32 . 33 . 34 . 35 . 26 . 27 . 38 . 39 . 40 . 41 . 42 . 43 . 44 . 45 . 46 . 47 .

ZUCRERMAN, S . in The Suprarenal Cortez, J . M . Yoffny (ed) p . 69, Academic Press, New York (1953) . ZUCR88MAN, S . CIHA Foundation Confereacn, Colloquia on Endocrinology 4 : 213 :228 (1952) . JONES, I . Cheater . Brit . Mad . Bull . 11 :156-160 (1953) . RAM~~ , J .A . Endocrinology 92 :881-887 (1973) . GORSRI, M .E . and I .E . LAWTON, Endocrinology 93 :1232-1234 (1973) . N~ûII~I, L .G . and N .B . SCHWARTZ, Endocrinology 88 :325-331 (1971) . FEDA, H .H ., R . BROWN-GRANT and C .S . CO1tIOIR . J . Endocrinology 50 :29-39 (1971) . FEDER, H .H . and R .B . RUF, Endocrinology 84 :171-174 (1969) . YANG, W .H ., W .P . YANG and L .L . LIN, Endocrinology 84 :1282-1285 (1969) . RAMIL~ , J .A . and A. PARIS, Neuroeadocriaology , in preae 1974 . TEOMAN, E .B ., M . SPROUL, B . SSELER and 3 . LEVINE, J . Endocrin . 46 :297-303 (1970) . HAGINO, N ., J .A . RAMAT-~ and R .A . GORSRI, Endocrinology 79 :451-454 (1966) . EVERETT, J .W . and C . H . SAWYER, Endocrin . 47 :198-218 (1950) . RAM.s~ .-~ , J .A . and E .L . BUNK, Endocrin . 91 :611-613 (1972) . GORSRI, M . and L E . LAWTON, Biol . Rausod . 7 :112 (1972) (abstract) . MANDL, A.M . J . R*±dnr_rin , 11 :359-368 (1954) . RAPS, D ., P . L . BARTHE 8nd P .A . DeBAULLES, fparis fin 27 ;339-341 (1971) . CRITCHLOW, V ., R .A . LIEBEIT, M . HAR-SELA, W . MOUNTCASTLE and H .S . LIPSCOMS Am . J . Phye1o1 .205 :807-815 (1963) . DUNK, J ., L . SCHEVING and P . MILLET, Am . J . Phvsio1 .223 :402-406 (1972) . rtsx~T .av ~ J .A . Steroide 21 :433-442 (19=3) . RAMAT-~ , J .A . Steroide 20 :185-197 (1972) . RAMIRSZ, V .D . in Handbook of Physiology , Section 2, Volume II, Par 1, American Physiological Society, Washington, D .C . 1973, Chapter 1 . TAYIAR, F .B . Acta . Sndocr . Co~enh . 35 :361-374 (1961) . ALD~i, R .H . Anat . Rec . 97 :1-19 (1947) . RAMALSY, J .A . and D . HARTOSIR, Proc . of the Endocrine Society , 1974 . RAIi~~-~ , J .A . and E .L . BUNK, Neuroeadocria 12 :257-271 (1973) . McCORMACR, C .E . and R.R. MEYER, Endocrin . 3 :300-307 (1963) . YING, S-Y and R.R . MEYER, Steroide 20 :237-245 (1972) . YING, S-Y and R.R . MEYBbt, Acta . Endocrin . 72 :161-172 (1973) . YING, 3-Y and R.R . MEYER, Endocrin . 84 :1466-1474 (1969) . CHRISTIAN, J .J ., Proc . Nat . Aça . Sçi . 47 :428-449 (1961) . CHRISTIAN, J .J ., Proc . Soc . Erz _ Biol . Med . 104 :330-332 (1960) . HAGIIiO, N ., Jan J . Physiol . 18 :350-358 (1968) . HAGINO, N ., M . itATANAHE, and J .W . GOLDZISHER, Endocrin . 84 :308-314 (1969) . HAGINO, N ., J . Clin. Endocrin . Metab . 34 :716-721 (1972) . CHRISTIAN, J .J ., Endocrin . 74 :669-674 (1964) . HAGINO, N ., Jav . J . Phvaiol . 17 :190-199 (1967) . SHITS, E .R ., J . JOHNSON, R .F . WEICR, 3 . LEVINE and J .M . DAVIDSON, Neuroeadocrin . 8 :94-106 (1971) . JOHNSON, J .J . and S . LEVINE, Neuroendocrin . 11 :268-273 (1973) . SMITH, E .R ., R . DOMINQUEZ and S . LEVINE, Neuroendocrin . 12 :41-51 (1973) . PARIB, A.L . and J .A . RAMALEY, Fertil 6 Steril . 24 :540-545 (1972) . ~r.xy , Fertil . 6 Steril . 24 :546-552 (1972) . PARIS, A ., P . RELLY and J .A . CRITCHLOW, V . and M.E . BAR-SELA in Neuroeadacr~ology ade . L . Martini and W .F . Gaaong, Academic Prnse, New York, Vol 2, pp . 101-162, 1967 . MANN, D . and C . HARRACLOUGH, Proc . Soc . EE~m . io . M~1 . 142 :1226-1228(1973) . CHUlIG, R .W ., J .E . ALLISON, A .J . STANLEY and L .G . G~1tFCR, Fertil . 6 Steril . 24 :677-686 (1973) . WERK, E .E ., L .J . SHOLITON and L . RALEJB, New J En g. J . Mad . 289!767-773 x973) . PIVA, F ., P . GAGLIANO, M . MOTTA 8nd L . MARTINI, R^eierr;n . 93 ;1178-1184 (1973) .

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48 . 49 .

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Am . Zooloaiet 12 :257-271 (1972) . MEIER, A.H . and R. MacGREGOR, y COYNE, M.D . and J .I . RITAY, Endocrin . 85 :1097-1102 (1969) .

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