566 



PHYSIOLOGY OF GONADS 



the morphologic and physiologic features 

 that are known for anovulatory and ovula- 

 tory cycles can be reproduced in castrated 

 monkeys by estrogen and progesterone. 



If one designs an experiment to simulate 

 the normal cycle in a castrated monkey 

 then estrogen should be given first to de- 

 velop the conditions of the follicular phase 

 followed by progesterone for the progesta- 

 tional development of the luteal phase. Ex- 

 perience has shown that this is the most ef- 

 fective procedure for the production of a 

 progestational endometrium. Progesterone, 

 as compared with estrogen, is a weak growth 

 jH'omoter and although it can produce pro- 

 gestational changes in the atrophic endome- 

 trium of a castrated monkey when given in 

 large doses, its action is greatly facilitated 

 when preceded by estrogen. The first ex- 

 periments in which progesterone was used 

 for this purpose were planned on this prin- 

 ciple (Hisaw, Meyer and Fevold, 1930; Hi- 

 saw, 1935; Engle, Smith and Shelesnyak, 

 1935). 



The first noticeable effect of progesterone 

 is an elongation of the epithelial cells of the 

 surface membrane and necks of the glands. 

 When the treatment is continued, this ef- 

 fect progresses down the gland towards the 

 base. This change is followed closely by a 

 rearrangement of the nuclei which is more 

 pronounced in the glands than in the surface 

 epithelium. The nuclei under the influence 

 of estrogen in doses which reproduce the 

 conditions of the follicular phase of a nor- 

 mal cvcle, are situated niostlv in the basal 



Fig. 9.8. Uterus of a castratefl monkey which 

 was given 2 mg. progesterone daily tor 113 days. 

 The endometrium is thin but bleeding occiu\s when 

 such treatment is stopped. The myometrimn is 

 soft and pliable and ilir l)lood vessels are cnlarsed 

 and have thick wails. 



half of the cells, some of them touching the 

 basement membrane. The nuclei retreat 

 from the basement membrane when proges- 

 terone is given leaving a conspicuous clear 

 zone. This zone is produced by intracellular 

 deposits of glycogen. These early changes 

 usually appear before pronounced spiraling 

 and dilation of the glands. 



Secretion begins in response to estrogenic 

 stimulation and increases greatly as pro- 

 gestational changes are established. It ap- 

 pears first in the necks of the glands and 

 progresses basalward. The surface epithe- 

 lium takes a less conspicuous part in secre- 

 tion and is usually reduced to a thin mem- 

 brane when injections of progesterone are 

 continued until a fully developed progesta- 

 tional endometrium is established. This pro- 

 gressive action of progesterone is such that 

 it is possible to find all conditions in a single 

 gland from active secretion and fraying in 

 the neck region through primary swelling to 

 an unmodified condition at the base. 



When treatment is continued for 25 to 30 

 days at doses of about 2.0 mg. daily, the 

 glands enter a state that has been called 

 "secretory exhaustion" (Hisaw, 1935). This 

 condition also is seen first in the necks of 

 the glands and progresses toward the base. 

 The glandular epithelium decreases in 

 thickness, and active secretion, as judged 

 by fraying of the cells, is absent. The glands 

 may become narrow and straight and the 

 endometrium may resemble that in castra- 

 tion atrophy. These involutionary changes 

 become even more pronounced if the treat- 

 ment is continued for several months or a 

 year (Fig. 9.8). The endometrium by this 

 time is extremely thin. The glands are 

 straight, short, and narrow, and the stroma 

 very dense. The myometrium is thick in pro- 

 portion to the endometrium and the uterine 

 blood vessels are large and have greatly 

 thickened walls. Such uteri tend to be some- 

 what smaller than normal and are soft and 

 pHable. 



Thus, it is seen that when growth is pro- 

 duced in tlie endonietiiuni of a castrated 

 monkey by giving estrogen and then con- 

 tinued on injections of progesterone, there 

 follows a sequential development of all 

 stages of the luteal phase of a normal men- 

 stiual cycle terminating in secretory ex- 

 haustion. However, this condition cannot 



