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Pathophysiology I: role of ovarian steroids
David R Rubinow and Peter J Schmidt
INTRODUCTION
A comprehensive review of the early endocrine studies
of premenstrual syndrome (PMS) was performed by
Reid and Yen 1 and, as described elsewhere, 2 most of
these studies suffered from methodologic flaws, including
the use of inadequate diagnostic criteria. PMS is a
time-oriented not a symptom-oriented diagnosis and
requires prospective demonstration that symptom appearance
is confined primarily to the luteal phase of the
woman’s menstrual cycle. Since 1983, the use of two
sets of diagnostic guidelines – Diagnostic and Statistical
Manual of Mental Disorders, fourth edition (DSM-
IV), 3 and National Institute of Mental Health (NIMH)
Premenstrual Syndrome Workshop Guidelines, unpublished
work 4 – has permitted greater homogeneity of
samples across studies, a requirement for comparison,
and generalization of results obtained. Data subsequently
generated provide little if any evidence for a role of
hormone excess or deficiency in the etiology of PMS.
Hormonal studies in women with PMS have employed
several different strategies:
● examination of symptoms after the administration
of hormones hypothesized to be deficient in women
with PMS
● measurement of basal hormone levels at selected
points in the menstrual cycle
● evaluation of dynamic endocrine function employing
frequent serial monitoring of hormone secretion
or endocrine challenge paradigms
● manipulation of menstrual cycle physiology in order
to examine the plasticity of the linkage between the
menstrual cycle and PMS symptoms.
The most frequently employed strategy has been the
comparison of luteal phase basal hormone levels with
those from the follicular phase in women with PMS or
with comparable values from a non-PMS control group.
In this chapter we focus on the roles of ovarian
steroids in the pathophysiology of PMS. Additionally, we
include studies investigating hypothalamic–pituitary–
adrenal (HPA) axis function in PMS, since this axis is
regulated by ovarian steroids, and abnormalities of HPA
axis function are reported in PMS. First, we provide
background information reviewing the physiology of
ovarian steroids and their cellular mechanisms of action.
Secondly, we describe examples of the neuromodulatory
actions of gonadal steroids in both preclinical and human
studies. Thirdly, we focus on the regulatory effects of
gonadal steroids on systems relevant to the pathophysiology
of PMS and affective adaptation, including a
section on the regulatory effects of ovarian steroids on
HPA axis function. Finally, we present studies on the
role of ovarian hormones in PMS categorized on the
basis of the research strategies employed.
GONADAL STEROID HORMONES
Synthesis and metabolism
Gonadal steroids, like all steroid hormones, are derivatives
of cholesterol. Steroidogenic acute regulatory
protein (STAR) is the critical regulator of cholesterol’s
availability within the mitochondria, where it is converted
by the enzyme cholesterol desmolase to pregnenolone.
5,6 Pregnenolone then serves as the precursor
for the whole family of steroid hormones, individual
members of which are generated through the actions of
a relatively small number of enzymes with multiple
sites of action (Figure 10.1). The resulting end products
of this cascade are determined by the tissue in which
the metabolism is occurring and the enzymes present in
that tissue. For example, testosterone may be the end
product and act directly at the androgen receptor, or it
may be reduced to a form with greater affinity for the
androgen receptor (dihydrotestosterone), converted to