Progesterone: the forgotten hormone in men?

Aging Male. 2004 Sep;7(3):236-57.

Oettel M, Mukhopadhyay AK.

Abstract

'Classical' genomic progesterone receptors appear relatively late in phylogenesis, i.e. it is only in
birds and mammals that they are detectable. In the different species, they mediate manifold
effects regarding the differentiation of target organ functions, mainly in the reproductive system.
Surprisingly, we know little about the physiology, endocrinology, and pharmacology of
progesterone and progestins in male gender or men respectively, despite the fact that, as to
progesterone secretion and serum progesterone levels, there are no great quantitative differences
between men and women (at least outside the luteal phase). In a prospective cohort study of 1026
men with and without cardiovascular disease, we were not able to demonstrate any age-
dependent change in serum progesterone concentrations. Progesterone influences
spermiogenesis, sperm capacitation/acrosome reaction and testosterone biosynthesis in the
Leydig cells. Other progesterone effects in men include those on the central nervous system
(CNS) (mainly mediated by 5alpha-reduced progesterone metabolites as so-called neurosteroids),
including blocking of gonadotropin secretion, sleep improvement, and effects on tumors in the
CNS (meningioma, fibroma), as well as effects on the immune system, cardiovascular system,
kidney function, adipose tissue, behavior, and respiratory system. A progestin may stimulate
weight gain and appetite in men as well as in women. The detection of progesterone receptor
isoforms would have a highly diagnostic value in prostate pathology (benign prostatic
hypertrophy and prostate cancer). The modulation of progesterone effects on typical male targets
is connected with a great pharmacodynamic variability. The reason for this is that, in men, some
important effects of progesterone are mediated non-genomically through different molecular
biological modes of action. Therefore, the precise therapeutic manipulation of progesterone
actions in the male requires completely new endocrine-pharmacological approaches.

NORMAL MALE & FEMALE REFERENCE LEVELS

It is a good idea to be a partner in the management of your hormonal health. The more you know about it
the better off you will be. One thing that can be of enormous assistance in understanding what your
doctors are talking about is to simply know what the "normal" reference ranges are for the various
hormones often discussed when talking about HRT therapies.

Be aware, however, that every laboratory establishes its OWN reference ranges that compensate for
calibration errors in equipment or for their own methodology. What is frustrating is that, instead of
adjusting their results and rendering them in some "standardized" fashion, each lab, instead, establishes
an "adjusted reference range." This effectively makes direct comparisons of results from one lab with
another impossible!
The numbers provided here are "ballpark" figures. When you get test results for hormone levels from
your doctors make sure you ask what the normal reference ranges are (for both male and female). That
way you can determine for yourself if you are in the upper, middle, or lower portion of those ranges and
you'll be armed with the information to discuss adjustments to your medication with your doctor. A
knowledge of what each hormone's role is would also be helpful, so I am including a brief description for
each hormone of the relevance to an IS or TS patient. The following all refer to serum (blood) test levels.

You may also notice that most of the hormone levels are the same range for both males and
postmenopausal women. Most male-to-female transsexual patients essentially are starting from the
postmenopausal/male range. The goal of their hormone therapy is to simulate levels within the normal
FOLLICULAR phase range for a woman. There is no health advantage in simulating a woman's menstral
cycle and chemically inducing PMS-like symptoms. The goal should be a stable level within the target
reference range. Female-to-male transsexual patients would obviously be shooting for the
postmenopausal and/or male ranges.

Dihydrotestosterone (DHT). This is a more potent form of testosterone that is metabolized by the body
from other androgens. In men most is made from testosterone, while in women the main source is
androstenedione (which is first converted INTO testosterone). Current research indicates that DHT is
responsible for male-pattern balding and excessive, unwanted hair in both sexes. In males it is also
responsible for non-cancerous prostate swelling (BPH).

DHT LEVELS
SEX pg/ml

Females:

Premenopausal 24-368

Postmenopausal 10-181

Males: 250-990

LDL - this is the so-called "Bad cholesterol" and may be a factor for some people. Estrogen therapy tends
to lower the LDL level while testosterone therapy makes it go up. If you have a high LDL level and are on
TRT therapy, you may have to make adjustments to diet or take other medications to address it.
LDL CHOLESTEROL LEVELS
160 mg/dL or more HIGH

130 to 159 mg/dL BORDERLINE

100 to 129 mg/dL NEAR OPTIMAL

Less than 100 mg/dL OPTIMAL

source: National Cholesterol Education Program

Estradiol (E2) - this is the main "female" hormone. There are two others, Estriol and Etrone, that are also
sometimes tested, but they are metabolized from Estradiol, so it is usually the main one checked. The full
name is 17-beta-Estradiol, which is also available in several medications for ERT therapy. Current
research indicates that, in some people, this hormone may play a role in the loss of bone density,
prevents male bodies from clearing DHT out of the prostate gland, and can stimulate estrogen-sensitive
tumor growth (if estrogen-sensitive cancer cells are already present).
 ESTRADIOL LEVELS
SEX pg/ml

Women (> 18 years old)

Follicular Phase 30-120

Ovulatory Peak 130-370

Luteal Phase 70-250

Post-Menopausal 15-60

Male 15-60

Progesterone (Pg) - This steroid hormone is a female sex hormone which, in conjunction with
estrogens, regulates the accessory organs during the menstrual cycle and it is particularly important in
preparing the endometrium for the implantation of the blastocyte and in maintaining pregnancy. In non
pregnant women progesterone is mainly secreted by the corpus luteum
whereas in pregnancy the placenta becomes the major source. Minor sources are the adrenal cortex for
both sexes and the testes for males. Current research indicates it balances agaisnt overactivity of both
testosterone and estrogen, and effectively blocks 5-alpha-reductase enzymatic conversion of
testosterone into DHT. Progesterone also plays a role in stimulationg Osteoblast (bond building)
enzymes, lowering cholesterol levels, stimulating growth of epithelial tissue and lobule-alveolar systems
in the breasts, and upregulation of the P-53 cell-division gene, thus offering an anti-carcinogenic effect
against run-away cell division in hormone sensitive tumors.

PROGESTERONE LEVELS
SEX ng/ml nmol/l

Females

Follicular phase 0.2-1.4 0.64 - 4.45

Luteal phase 4 - 25 12.7 - 79.5

Post-Menopausal 0.1 - 1 0.32 - 3.18

Males 0.1 - 1 0.32 - 3.18

Conversion factor: 1 ng/ml = 3.18 nmol/l

Testosterone (T) - one of the most important male sex hormones. In men it is mainly synthesized by the
testes, in women both the ovaries and by the adrenal cortex; it is secreted into circulation. Testosterone is
transported in the plasma by a beta-globulin, called testosterone binding
globulin. It is estimated that about 98 % of the circulating testosterone is bound. The remainder, present
as free testosterone, is assumed to be the metabolicly active portion. In the target organ, it is transformed
by 5-alpha-reductase into the physiologically effective androgen DHT. In men the determination of
testosterone is used as an indicator for the function of the testes: low hormone levels are found in cases
with Klinefelter's syndrome, cryptorchism or anorchia. Male or female patients with an androgen
producing tumor (ovaries, adrenal cortex, testes) show
increased values. Measurement of testosterone is used to confirm hirsutism in woman. The determination
of free or not specifically protein-bound testosterone can be helpful in cases of hyperprolactinemic women
or hyperandrogenism. It promotes the burning of fat and the building of lean muscle mass. It also appears
to be the fuel for the libido in both sexes. The role of testosterone in cardiovascular health is still hotly
debated, but it appears that it may have a detrimental effect over the long term. Testosterone, like
progesterone, upregulates the P-53 gene to turn off rampant cellular division, so in that sense is anti-
carcinogenic. Testosterone also stimulates oil production in the skin, which can lead to acne problems.

TOTAL TESTOSTERONE LEVELS

SEX ng/dl ng/ml

Females 6 - 86 0.1 - 1.2

Males 270 - 1100 2.4 - 12

Conversion factor: 1 ng/ml = 3.47 nmol/l

Free or Unbound Testosterone ("Free T") - As mentioned above, about 98% of the testosterone in a
man or woman's body is bound to blood proteins. This means that only a small portion is actually "bio-
available" and acting on the body's tissues. A healthy percentage for either men or women is around
2.5%. One thing that sometimes frustrates gender patients is that the measurements for the biologically
significant free testosterone are not easily compared between men and women. Labs often will state the
percentage free for men, but give a measurement in pg/ml for women. Or the male measurements will be
in ng/dl requiring a mathematical conversion for direct comparison to the "normal" range of the opposite
sex. The percentage is usually higher in adolescents (up to 5%) and quite low in elderly people (around
1%). Many doctors believe that any reading below 2% means the patient should take testosterone
supplements, and that any reading below 1% indicates a completely absent sex drive. The level readings
between men and women are so vastly different because the number represents a percentage of the
TOTAL testosterone. Women naturally start with a lower total amount, so 2.5% of 40ng/dl is going to be
much less than 2.5% of 800ng/dl in a man.

FREE TESTOSTERONE LEVELS

SEX ng/dl pg/ml % Free Range

Females 0.3-1.9 0.6 - 6.8 0.4 - 2.4

Males 9-30 47.0-244.0 1.6 - 2.9

Total Free Range is 0.3 - 5% ( 2% average )

CLICK HERE for sample reference ranges for other free/bioavailable hormone levels.

DHEA-S (Dehydroepiandrosterone sulfate) is secreted by the adrenal cortex. DHEA-S

is thought to be a biologically weak androgen, but because of its high concentration in blood, it
contributes significantly to the androgenization process. The physiological role of DHEA-S is not well
known, but it seems to be intricately involved in adrenarche (axillary and pubic hair growth). DHEA-S
appears to be an excellent indicator of adrenal androgen production. Elevated levels of DHEA-S have
been reported in states of excess androgen production such as cystic acne, hirsutism, infertility,
enzymatic adrenal defects, Cushing's syndrome due to bilateral adrenal hyperplasia, and virilizing adrenal
tumors.

DHEA-S SERUM LEVELS

 SEX µg/ml µmol/l

Females

Premenopausal 0.8 - 3.9 2.1 - 10.1

Pregnancy (3. Trimenon) 0.2 - 1.2 0.5 - 3.1

Postmenopausal 0.1 - 0.6 0.3 - 1.6

Newborns (both sexes) 1.7 - 3.6 4.4 - 9.4

Males 1.0 - 4.2 2.6 - 10.9

Conversion factor: 1 µg/ml = 2,6 µmol/l

Androstenedione - this hormone is produced by the adrenals and gonads. Therefore, the determination
of the level of androstenedione in serum is important in the evaluation of the functional state of the
glands. Androstenedione is a precursor of testosterone and estrone. Besides the adrenals, in females,
the ovaries have been shown to be an important source of androstenedione during the ovulatory
cycle.The principle production of testosterone in females is from the conversion of other related
androgens, especially androstenedione. An abnormal testosterone level in women should be
accompanied by the estimation of serum androstenedione. The use of serum testosterone determination
in conjunction with Enzyme Immunoassay of androstenedione can be used to determine if source of
excess androgen production is adrenal or ovarian.

ANDROSTENEDIONE LEVELS
SEX Mean [ng/ml] Absolute Range [ng/ml]

Females (18-49 years) 2.15 0.70 - 3.50

Females (50-80 years) 1.80 0.20 - 3.40

Males 1.75 0.35 - 3.15

Conversion factor: To convert to nmol/L: ng/ml x 3.45 = nmol/l

Leutenizing Hormone (LH) -LH stimulates Leydig cells in the testes to produce and secrete testosterone
(T). As the testosterone travels through the bloodstream it passes through the anterior pituitary gland and
hypothalamus it creates a "negative feedback loop" that triggers a decrease in GnRH and LH. LH also
stimulates the adrenal gland to produce androstenedione and progesterone. A problem with LH levels
alone is rarely seen, so testing is only needed if testosterone level is abnormal, for example, if the patient
is suspected to have been born with Klinefelters Syndrome. In women a normal LH level is similar to FSH.
An LH that is higher than FSH is one indication of PCOS.

LH LEVELS
SEX mIU/ml

Females (follicular) <7

Females (Surge 48 hours before ovulation) > 20

 Males 2 - 18

Follicle Stimulating Hormone (FSH) - In women FSH is often used as a gauge of ovarian reserve. In
general, under 6 is excellent, 6-9 is good, 9-10 fair, 10-13 diminished reserve, 13+ very hard to stimulate.
In PCOS testing, the LH:FSH ratio may be used in the diagnosis. The ratio is usually close to 1:1, but if
the LH is higher, it is one possible indication of PCOS. Basic hormone testing for males often only
includes testosterone and FSH. However, in cases such as Klinefelters Syndrome doctors will usually
look at both FSH and LH levels. In males FSH stimulates the Sertoli cells in the testes to produce
androgen-binding proteins, testosterone, and a protein called inhibin. Inhibin, in turn, travels in the blood
back to the pituitary gland whre it creates a "negative feedback loop" that decreases the output of FSH.
Since FSH stimulates testosterone production, and testosterone can be converted to DHT and estradiol,
an increase of any or all three can also create a "feedback loop" that decreases FSH secretion.

FSH LEVELS
SEX mIU/ml

Females 3-20
Males 1-18

Sex Hormone Binding Globulin (SHBG) - this is the principle blood protein that ties up the bulk of the
steroids the body produces. For example, it bind with about 98% of the total testosterone, but also binds
with other steroids as well. As androgen production increases, available SHBG decreases.

SHBG LEVELS
SEX nmol/l

Females 18-114
Males 7-50